Aminopyrimidine derivatives as lrrk2 modulators

ABSTRACT

Compounds of the formula I: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof,
 
wherein A, X, R 1 , R 2 , R 3  and R 4  are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson&#39;s disease.

CROSS REFERENCE TO RELATED APPLICATION

This Application claims the benefit under 35 USC §119 of U.S.Provisional Application Ser. No. 61/564,759 filed on Nov. 29, 2011, thedisclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention pertains to compounds that modulate the function of LRRK2and are useful for treatment of LRRK2-mediated diseases and conditionssuch as Parkinson's disease.

BACKGROUND OF THE INVENTION

Neurodegenerative diseases such as Parkinson's disease, Lewy bodydementia and Huntington's disease affect millions of individuals.Parkinson's disease is a chronic, progressive motor system disorder thatafflicts approximately one out of every 1000 people, with hereditaryParkinson's disease accounting for 5-10% of all of patients. Parkinson'sdisease is caused by progressive loss of mid-brain dopamine neurons,leaving patients with impaired ability to direct and control theirmovements. The primary Parkinson's disease symptoms are trembling,rigidity, slowness of movement, and impaired balance. Many Parkinson'sdisease patients also experience other symptoms such as emotionalchanges, memory loss, speech problems, and sleeping disorders.

The gene encoding the leucine-rich repeat kinase 2 protein (LRRK2) hasbeen identified in association with hereditary Parkinson's disease(Paisan-Ruiz et al., Neuron, Vol. 44(4), 2004, pp 595-600; Zimprich etal., Neuron, Vol. 44(4), 2004, 601-607). In-vitro studies show thatParkinson's disease-associated mutation leads to increased LRRK2 kinaseactivity and decreased rate of GTP hydrolysis compared to wild-type (Guoet al., Experimental Cell Research, Vol. 313(16), 2007, pp. 3658-3670.Anti-LRRK2 antibodies have been used to label brainstem Lewy bodiesassociated with Parkinson's disease and cortical antibodies associatedwith Lewis body dementia suggesting that LRRK2 may play an importantrole in Lewie body formation and pathogenesis associated with thesediseases (Zhou et al., Molecular Degeneration, 2006, 1:17doi:10.1186/1750-1326-1-17). LRRK2 has also been identified as a genepotentially associated with increased susceptibility to Crohn's diseaseand susceptibility to leprosy (Zhang et al., New England J. Med. Vol.361 (2009) pp. 2609-2618.

LRRK2 has also been associated with the transition of mild cognitiveimpairment to Alzheimer's disease (WO2007/149789); L-Dopa induceddyskinesia (Hurley et al., Eur. J. Neurosci., Vol. 26, 2007, pp.171-177; CNS disorders associated with neuronal progenitordifferentiation (Milosevic et al., Neurodegen., Vol. 4, 2009, p. 25);cancers such as kidney, breast, prostate, blood and lung cancers andacute myelogenous leukemia (WO2011/038572); papillary renal and thyroidcarcinomas (Looyenga et al.,www.pnas.org/cgi/doi/10.1073/pnas.1012500108); multiple myeloma (Chapmanet al., Nature Vol. 471, 2011, pp. 467-472); amyotrophic lateralsclerosis (Shtilbans et al., Amyotrophic Lateral Sclerosis “Early Online2011, pp. 1-7); rheumatoid arthritis (Nakamura et al., DNA Res. Vol.13(4), 2006, pp. 169-183); and ankylosing spondylytis (Danoy et al.,PLoS Genetics, Vol. 6(12), 2010, e1001195, pp. 1-5).

Accordingly, compounds and compositions effective at modulating LRRK2activity may provide a treatment for neurodegenerative diseases such asParkinson's disease and Lewie body dementia, for CNS disorders such asAlzheimer's disease and L-Dopa induced dyskinesia, for cancers such askidney, breast, prostate, blood, papillary and lung cancers, acutemyelogenous leukemia and multiple myeloma, and for inflammatory diseasessuch as leprosy, Crohn's disease, amyotrophic lateral sclerosis,rheumatoid arthritis, and ankylosing spondylytis. Particularly, there isa need for compounds with LRRK2 affinity that are selective for LRRK2over other kinases, such as JAK2, and which can provide effective drugsfor treatment of neurodegenerative disorders such as Parkinson'sdisease.

SUMMARY OF THE INVENTION

The invention provides compounds of the formula I:

or pharmaceutically acceptable salts thereof,wherein:

A is a five- or six-membered saturated or unsaturated ring that includesone or two heteroatoms selected from O, N and S, which is substitutedonce with R⁵, and which is optionally substituted one, two or threetimes with R⁶;

X is: —NR^(a)—; —O—; or —S(O)_(r)— wherein r is from 0 to 2 and R^(a) ishydrogen or C₁₋₆alkyl;

R¹ is: C₁₋₆alkyl; C₁₋₆alkenyl; C₁₋₆alkynyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted withC₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portionis optionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl;

or R¹ and R^(a) together with the atoms to which they are attached mayform a three to six membered ring that may optionally include anadditional heteroatom selected from O, N and S, and which is substitutedwith oxo, halo or C₁₋₆alkyl;

R² is: halo; C₁₋₆alkoxy; cyano; C₁₋₆alkynyl; C₁₋₆alkenyl;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; acetyl; oxetanyl; or oxetan-C₁₋₆alkyl;

one of R³ and R⁴ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; C₃₋₆cycloalkyloxy;halo-C₁₋₆alkyl; or halo-C₁₋₆alkoxy, and the other is hydrogen;

R⁵ is; oxo; C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl; or—C(O)—NR^(b)R^(c) wherein R^(b) and R^(c) each independently is hydrogenor —C₁₋₆alkyl, or R^(b) and R^(c) together with the atoms to which theyare attached may form a heterocyclyl group that optionally includes anadditional heteroatom selected from O, N and S and which is optionallysubstituted one or more times with R⁶; and

each R⁶ is independently: C₁₋₆alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; halo; halo-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; heterocyclyl; oxo; or —C(O)—NR^(b)R^(c).

The invention also provides and pharmaceutical compositions comprisingthe compounds, methods of using the compounds, and methods of preparingthe compounds.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms, i.e. C₁-C₆alkyl. Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one double bond, e.g., ethenyl,propenyl, and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one triple bond, e.g., ethynyl,propynyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkoxy” and “alkyloxy”, which may be used interchangeably, mean amoiety of the formula —OR, wherein R is an alkyl moiety as definedherein. Examples of alkoxy moieties include, but are not limited to,methoxy, ethoxy, isopropoxy, and the like.

“Alkoxyalkyl” means a moiety of the formula R^(a)—O—R^(b)—, where R^(a)is alkyl and R^(b) is alkylene as defined herein. Exemplary alkoxyalkylgroups include, by way of example, 2-methoxyethyl, 3-methoxypropyl,1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and1-(2-methoxyethyl)-3-methoxypropyl.

“Alkoxyalkoxy” means a group of the formula —O—R—R′ wherein R isalkylene and R′ is alkoxy as defined herein.

“Alkylcarbonyl” means a moiety of the formula —C(O)—R, wherein R isalkyl as defined herein.

“Alkoxycarbonyl” means a group of the formula —C(O)—R wherein R isalkoxy as defined herein.

“Alkylcarbonylalkyl” means a group of the formula —R—C(O)—R wherein R isalkylene and R′ is alkyl as defined herein.

“Alkoxycarbonylalkyl” means a group of the formula —R—C(O)—R wherein Ris alkylene and R′ is alkoxy as defined herein.

“Alkoxycarbonylalkoxy” means a group of the formula —O—R—C(O)—R′ whereinR is alkylene and R′ is alkoxy as defined herein.

“Hydroxycarbonylalkoxy” means a group of the formula —O—R—C(O)—OHwherein R is alkylene as defined herein.

“Alkylaminocarbonylalkoxy” means a group of the formula —O—R—C(O)—NHR′wherein R is alkylene and R′ is alkyl as defined herein.

“Dialkylaminocarbonylalkoxy” means a group of the formula—O—R—C(O)—NR′R″ wherein R is alkylene and R′ and R″ are alkyl as definedherein.

“Alkylaminoalkoxy” means a group of the formula —O—R—NHR′ wherein R isalkylene and R′ is alkyl as defined herein.

“Dialkylaminoalkoxy” means a group of the formula —O—R—NR′R′ wherein Ris alkylene and R′ and R″ are alkyl as defined herein.

“Alkylsulfonyl” means a moiety of the formula —SO₂—R, wherein R is alkylas defined herein.

“Alkylsulfonylalkyl means a moiety of the formula —R′—SO₂—R″ where whereR′ is alkylene and R″ is alkyl as defined herein.

“Alkylsulfonylalkoxy” means a group of the formula —O—R—SO₂—R′ wherein Ris alkylene and R′ is alkyl as defined herein.

“Amino means a moiety of the formula —NRR′ wherein R and R′ eachindependently is hydrogen or alkyl as defined herein. “Amino thusincludes “alkylamino (where one of R and R′ is alkyl and the other ishydrogen) and “dialkylamino (where R and R′ are both alkyl.

“Aminocarbonyl” means a group of the formula —C(O)—R wherein R is aminoas defined herein.

“Alkoxyamino” means a moiety of the formula —NR—OR′ wherein R ishydrogen or alkyl and R′ is alkyl as defined herein.

“Alkylsulfanyl” means a moiety of the formula —SR wherein R is alkyl asdefined herein.

“Aminoalkyl” means a group —R—R′ wherein R′ is amino and R is alkyleneas defined herein. “Aminoalkyl” includes aminomethyl, aminoethyl,1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of“aminoalkyl” may be substituted once or twice with alkyl to provide“alkylaminoalkyl” and “dialkylaminoalkyl” respectively.“Alkylaminoalkyl” includes methylaminomethyl, methylaminoethyl,methylaminopropyl, ethylaminoethyl and the like. “Dialkylaminoalkyl”includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,N-methyl-N-ethylaminoethyl, and the like.

“Aminoalkoxy” means a group —OR—R′ wherein R′ is amino and R is alkyleneas defined herein.

“Alkylsulfonylamido” means a moiety of the formula —NR′SO₂—R wherein Ris alkyl and R′ is hydrogen or alkyl.

“Aminocarbonyloxyalkyl” or “carbamylalkyl” means a group of the formula—R—O—C(O)—NR′R″ wherein R is alkylene and R′, R″ each independently ishydrogen or alkyl as defined herein.

“Alkynylalkoxy” means a group of the formula —O—R—R′ wherein R isalkylene and R′ is alkynyl as defined herein.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono-, bi- or tricyclic aromatic ring. The aryl group can beoptionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, phenyl, naphthyl, phenanthryl,fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl,methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl,diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl,benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl,benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl,methylenedioxyphenyl, ethylenedioxyphenyl, and the like, of which may beoptionally substituted as defined herein.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean aradical-R^(a)R^(b) where R^(a) is an alkylene group and R^(b) is an arylgroup as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

“Arylsulfonyl means a group of the formula —SO₂—R wherein R is aryl asdefined herein.

“Aryloxy” means a group of the formula —O—R wherein R is aryl as definedherein.

“Aralkyloxy” means a group of the formula —O—R—R″ wherein R is alkyleneand R′ is aryl as defined herein.

“Carboxy” or “hydroxycarbonyl”, which may be used interchangeably, meansa group of the formula —C(O)—OH.

“Cyanoalkyl” “means a moiety of the formula —R′—R″, where R′ is alkyleneas defined herein and R″ is cyano or nitrile.

“Cycloalkyl” means a monovalent saturated carbocyclic moiety consistingof mono- or bicyclic rings. Particular cycloalkyl are unsubstituted orsubstituted with alkyl. Cycloalkyl can optionally be substituted asdefined herein. Unless defined otherwise, cycloalkyl may be optionallysubstituted with one or more substituents, wherein each substituent isindependently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino,monoalkylamino, or dialkylamino. Examples of cycloalkyl moietiesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like, including partially unsaturated(cycloalkenyl) derivatives thereof

“Cycloalkylalkyl” means a moiety of the formula —R′—R″, where R′ isalkylene and R″ is cycloalkyl as defined herein.

“Cycloalkylalkoxy” means a group of the formula —O—R—R′ wherein R isalkylene and R′ is cycloalkyl as defined herein.

“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ringatoms having at least one aromatic ring containing one, two, or threering heteroatoms selected from N, O, or S, the remaining ring atomsbeing C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring maybe optionally substituted as defined herein. Examples of heteroarylmoieties include, but are not limited to, optionally substitutedimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl,pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl,isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl,benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl,triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl,naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyland the like, each of which may be optionally substituted as definedherein.

“Heteroarylalkyl” or “heteroaralkyl” means a group of the formula —R—R′wherein R is alkylene and R′ is heteroaryl as defined herein.

“Heteroarylsulfonyl means a group of the formula —SO₂—R wherein R isheteroaryl as defined herein.

“Heteroaryloxy” means a group of the formula —O—R wherein R isheteroaryl as defined herein.

“Heteroaralkyloxy” means a group of the formula —O—R—R″ wherein R isalkylene and R′ is heteroaryl as defined herein.

The terms “halo”, “halogen” and “halide”, which may be usedinterchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkylmoiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three or four heteroatoms(chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may beoptionally substituted as defined herein. Examples of heterocyclylmoieties include, but are not limited to, optionally substitutedpiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl,pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyland the like. Such heterocyclyl may be optionally substituted as definedherein.

“Heterocyclylalkyl” means a moiety of the formula —R—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Heterocyclyloxy” means a moiety of the formula —OR wherein R isheterocyclyl as defined herein.

“Heterocyclylalkoxy” means a moiety of the formula —OR—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Heterocyclylsulfonyl” means a group of formula —SO₂—R wherein R isheterocyclyl as defined herein.

“Hydroxyalkoxy” means a moiety of the formula —OR wherein R ishydroxyalkyl as defined herein.

“Hydroxyalkylamino” means a moiety of the formula —NR—R′ wherein R ishydrogen or alkyl and R′ is hydroxyalkyl as defined herein.

“Hydroxyalkylaminoalkyl” means a moiety of the formula —R—NR′—R″ whereinR is alkylene, R′ is hydrogen or alkyl, and R″ is hydroxyalkyl asdefined herein.

“Hydroxycarbonylalkyl” or “carboxyalkyl” means a group of the formula—R—(CO)—OH where R is alkylene as defined herein.

“Hydroxycarbonylalkoxy” means a group of the formula —O—R—C(O)—OHwherein R is alkylene as defined herein.

“Hydroxyalkyloxycarbonylalkyl” or “hydroxyalkoxycarbonylalkyl” means agroup of the formula —R—C(O)—O—R—OH wherein each R is alkylene and maybe the same or different.

“Hydroxyalkyl” means an alkyl moiety as defined herein, substituted withone or more, for example, one, two or three hydroxy groups, providedthat the same carbon atom does not carry more than one hydroxy group.Representative examples include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl

“Hydroxycycloalkyl” means a cycloalkyl moiety as defined herein whereinone, two or three hydrogen atoms in the cycloalkyl radical have beenreplaced with a hydroxy substituent. Representative examples include,but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.

“Alkoxy hydroxyalkyl” and “hydroxy alkoxyalkyl”, which may be usedinterchangeably, means an alkyl as defined herein that is substituted atleast once with hydroxy and at least once with alkoxy. “Alkoxyhydroxyalkyl” and “hydroxy alkoxyalkyl” thus encompass, for example,2-hydroxy-3-methoxy-propan-1-yl and the like.

“Urea” or “ureido” means a group of the formula —NR′—C(O)—NR″R′″ whereinR′, R″ and R′″ each independently is hydrogen or alkyl.

“Carbamate” means a group of the formula —O—C(O)—NR′R″ wherein R′ and R″each independently is hydrogen or alkyl.

“Carboxy” means a group of the formula —O—C(O)—OH.

“Sulfonamido” means a group of the formula —SO₂—NR′R″ wherein R′, R″ andR′″ each independently is hydrogen or alkyl.

“Optionally substituted” when used in association with an “aryl”,phenyl”, “heteroaryl” “cycloalkyl” or “heterocyclyl” moiety means thatsuch moiety may be unsubstituted (i.e., all open valencies are occupiedby a hydrogen atom) or substituted with specific groups as relatedherein.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Disease” and “Disease state” means any disease, condition, symptom,disorder or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. Theartisan in the art will know how to chose a group for the ease ofremoval and for the ability to withstand the following reactions.

“Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Parkinson's disease” means a degenerative disorder of the centralnervous system that impairs motor skills, speech, and/or cognitivefunction. Symptoms of Parkinson's disease may include, for example,muscle rigidity, tremor, slowing of physical movement (bradykinesia) andloss of physical movement (akinesia).

“Lewie body disease” also called “Lewie body dementia”, diffuse Lewybody disease”, cortical Lewie body disease”, means a neurogenerativedisorder characterized anatomically by the presence of Lewie bodies inthe brain.

“Subject” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as particular definitions, if any.

“Treating” or “treatment” of a disease state includes, inter alia,inhibiting the disease state, i.e., arresting the development of thedisease state or its clinical symptoms, and/or relieving the diseasestate, i.e., causing temporary or permanent regression of the diseasestate or its clinical symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature and Structures

In general, the nomenclature and chemical names used in this Applicationare based on ChembioOffice™ by CambridgeSoft™. Any open valencyappearing on a carbon, oxygen sulfur or nitrogen atom in the structuresherein indicates the presence of a hydrogen atom unless indicatedotherwise. Where a nitrogen-containing heteroaryl ring is shown with anopen valency on a nitrogen atom, and variables such as R^(a), R^(b) orR^(c) are shown on the heteroaryl ring, such variables may be bound orjoined to the open valency nitrogen. Where a chiral center exists in astructure but no specific stereochemistry is shown for the chiralcenter, both enantiomers associated with the chiral center areencompassed by the structure. Where a structure shown herein may existin multiple tautomeric forms, all such tautomers are encompassed by thestructure. The atoms represented in the structures herein are intendedto encompass all naturally occurring isotopes of such atoms. Thus, forexample, the hydrogen atoms represented herein are meant to includedeuterium and tritium, and the carbon atoms are meant to include C¹³ andC¹⁴ isotopes.

Compounds of the Invention

The invention provides compounds of formula I:

or pharmaceutically acceptable salts thereof,wherein:

A is a five- or six-membered saturated or unsaturated ring that includesone or two heteroatoms selected from O, N and S, which is substitutedonce with R⁵, and which is optionally substituted one, two or threetimes with R⁶;

X is: —NR^(a)—; —O—; or —S(O)_(r)— wherein r is from 0 to 2 and R^(a) ishydrogen or C₁₋₆alkyl;

R¹ is: C₁₋₆alkyl; C₁₋₆alkenyl; C₁₋₆alkynyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; amino-C₁₋₆alkyl;C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted withC₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portionis optionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl;

or R¹ and R^(a) together with the atoms to which they are attached mayform a three to six membered ring that may optionally include anadditional heteroatom selected from O, N and S, and which is substitutedwith oxo, halo or C₁₋₆alkyl;

R² is: halo; C₁₋₆alkoxy; cyano; C₁₋₆alkynyl; C₁₋₆alkenyl;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; acetyl; oxetanyl; or oxetan-C₁₋₆alkyl;

-   -   one of R³ and R⁴ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy;        C₃₋₆cycloalkyloxy; halo-C₁₋₆alkyl; or halo-C₁₋₆alkoxy, and the        other is hydrogen;

R⁵ is; oxo; C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl; or—C(O)—NR^(b)R^(c) wherein R^(b) and R^(c) each independently is hydrogenor —C₁₋₆alkyl, or R^(b) and R^(c) together with the atoms to which theyare attached may form a heterocyclyl group that optionally includes anadditional heteroatom selected from O, N and S and which is optionallysubstituted one or more times with R⁶; and

-   -   each R⁶ is independently: C₁₋₆alkyl; C₃₋₆cycloalkyl;        C₃₋₆cycloalkyl-C₁₋₆alkyl; halo; halo-C₁₋₆alkyl;        hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; heterocyclyl; oxo; or        —C(O)—NR^(b)R^(c).

In certain embodiments of formula I, R¹ and R^(a) together with theatoms to which they are attached may form a three to six membered ringthat may optionally include an additional heteroatom selected from O, Nand S, and which may be optionally substituted with oxo, halo orC₁₋₆alkyl.

In certain embodiments of formula I, R¹ and R^(a) together with theatoms to which they are attached form a five or six membered ring.

In certain embodiments of formula I, R¹ and R^(a) together with theatoms to which they are attached form a pyrrolidinyl, piperidinyl oroxazoladinonyl group.

In certain embodiments of formula I, R² is acetyl.

In certain embodiments of formula I, when R¹ is cyclopropyl, cyclobutyl,cyclopropyl-C₁₋₆alkyl or cyclobutyl-C₁₋₆alkyl, then X is —O—.

In certain embodiments of formula I, r is 0.

In certain embodiments of formula I, r is 2.

In certain embodiments of formula I, X is —NR^(a)- or —O—.

In certain embodiments of formula I, X is —NR^(a).

In certain embodiments of formula I, X is —O—.

In certain embodiments of formula I, X is —S(O)_(n)—.

In certain embodiments of formula I, X is —NH— or —O—.

In certain embodiments of formula I, R^(a) is hydrogen.

In certain embodiments of formula I, R^(a) is C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is: C₁₋₆alkyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; amino-C₁₋₆alkyl; C₁₋₆alkylsulfonyl-C₁₋₆alkyl;C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is: C₁₋₆alkyl; C₃₋₆cycloalkyloptionally substituted with C₁₋₆alkyl; or C₃₋₆cycloalkyl-C₁₋₆alkylwherein the C₃₋₆cycloalkyl portion is optionally substituted withC₁₋₆alkyl.

In certain embodiments of formula I, R¹ is: C₁₋₆alkyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; amino-C₁₋₆alkyl; C₁₋₆alkylsulfonyl-C₁₋₆alkyl;tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; oroxetan-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is: C₁₋₆alkyl; halo-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; amino-C₁₋₆alkyl; or C₁₋₆alkylsulfonyl-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is halo-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is amino-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is C₁₋₆alkylsulfonyl-C₁₋₆alkyloptionally substituted with C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is C₃₋₆cycloalkyl optionallysubstituted with C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is C₃₋₆cycloalkyl-C₁₋₆alkylwherein the C₃₋₆cycloalkyl portion is optionally substituted withC₁₋₆alkyl.

In certain embodiments of formula I, R¹ is tetrahydrofuranyl.

In certain embodiments of formula I, R¹ is tetrahydrofuranyl-C₁₋₆alkyl;oxetanyl.

In certain embodiments of formula I, R¹ is or oxetan-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is: methyl; ethyl; n-propyl;isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopropyl; cyclobutyl;cyclopentyl; cyclohexyl; cyclopropylmethyl; cyclobutylmethyl;cyclopentylmethyl; cyclopropylethyl; methoxyethyl; oxetanyl; ortetrahydrofuranylmethyl.

In certain embodiments of formula I, R¹ is: methyl; ethyl; n-propyl;isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl; cyclohexyl;cyclopropylmethyl; cyclobutylmethyl; cyclopentylmethyl;cyclopropylethyl; methoxyethyl; oxetanyl; or tetrahydrofuranylmethyl.

In certain embodiments of formula I, R¹ is: methyl; ethyl; n-propyl;isopropyl; isobutyl; 3,3-dimethylpropyl; cyclopentyl; cyclohexyl;cyclopentylmethyl; methoxyethyl; oxetanyl; or tetrahydrofuranylmethyl.

In certain embodiments of formula I, R¹ is: methyl; ethyl; n-propyl;isopropyl; or isobutyl.

In certain embodiments of formula I, R¹ is methyl or ethyl.

In certain embodiments of formula I, R¹ is methyl.

In certain embodiments of formula I, R¹ is ethyl.

In certain embodiments of formula I, R¹ is: cyclopropyl; cyclobutyl;cyclopentyl; cyclohexyl; cyclopropylmethyl; cyclobutylmethyl;cyclopentylmethyl; or cyclopropylethyl.

In certain embodiments of formula I, R¹ is: cyclopentyl; cyclohexyl; orcyclopentylmethyl.

In certain embodiments of formula I, R² is: halo; C₁₋₆alkoxy;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₃₋₆cycloalkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl wherein the C₃₋₆cycloalkyl portion isoptionally substituted with C₁₋₆alkyl; tetrahydrofuranyl;tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; or oxetan-C₁₋₆alkyl.

In certain embodiments of formula I, R² is: halo; C₁₋₆alkoxy;halo-C₁₋₆alkyl; cyano; C₁₋₆alkynyl; C₁₋₆alkenyl; C₃₋₆cycloalkyl; orC₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R² is: halo; C₁₋₆alkoxy;halo-C₁₋₆alkyl; cyano; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R² is: halo; C₁₋₆alkoxy;halo-C₁₋₆alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R² is: halo; halo-C₁₋₆alkyl; orcyano.

In certain embodiments of formula I, R² is: halo; or halo-C₁₋₆alkyl.

In certain embodiments of formula I, R² is halo.

In certain embodiments of formula I, R² is C₁₋₆alkoxy.

In certain embodiments of formula I, R² is halo-C₁₋₆alkoxy.

In certain embodiments of formula I, R² is halo-C₁₋₆alkyl.

In certain embodiments of formula I, R² is C₃₋₆cycloalkyl.

In certain embodiments of formula I, R² is C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R² is tetrahydrofuranyl.

In certain embodiments of formula I, R² is tetrahydrofuranyl-C₁₋₆alkyl.

In certain embodiments of formula I, R² is oxetanyl.

In certain embodiments of formula I, R² is oxetan-C₁₋₆alkyl.

In certain embodiments of formula I, R² is halo, trifluoromethyl orcyano.

In certain embodiments of formula I, R² is chloro, trifluoromethyl orcyano.

In certain embodiments of formula I, R² is chloro or trifluoromethyl.

In certain embodiments of formula I, R² is fluoro, chloro or bromo.

In certain embodiments of formula I, R² is chloro.

In certain embodiments of formula I, R² is fluoro.

In certain embodiments of formula I, R² is bromo.

In certain embodiments of formula I, R² is trifluoromethyl.

In certain embodiments of formula I, R² is methoxy.

In certain embodiments of formula I, R² is cyano.

In certain embodiments of formula I, R² is C₁₋₆alkynyl.

In certain embodiments of formula I, R² is C₁₋₆alkenyl.

In certain embodiments of formula I, R³ is: hydrogen.

In certain embodiments of formula I, R³ is: C₁₋₆alkyl.

In certain embodiments of formula I, R³ is halo.

In certain embodiments of formula I, R³ is C₁₋₆alkyl.

In certain embodiments of formula I, R³ is C₁₋₆alkoxy.

In certain embodiments of formula I, R³ is halo or C₁₋₆alkoxy.

In certain embodiments of formula I, R³ is C₃₋₆cycloalkyloxy.

In certain embodiments of formula I, R³ is halo-C₁₋₆alkyl.

In certain embodiments of formula I, R³ is halo-C₁₋₆alkoxy.

In certain embodiments of formula I, R³ is halo or methoxy.

In certain embodiments of formula I, R³ is fluoro, chloro or methoxy.

In certain embodiments of formula I, R³ is fluoro or chloro.

In certain embodiments of formula I, R³ is methoxy.

In certain embodiments of formula I, R³ is methyl

In certain embodiments of formula I, R³ is chloro.

In certain embodiments of formula I, R³ is fluoro.

In certain embodiments of formula I, R⁴ is: hydrogen.

In certain embodiments of formula I, R⁴ is: C₁₋₆alkyl;

In certain embodiments of formula I, R⁴ is halo.

In certain embodiments of formula I, R⁴ is C₁₋₆alkyl.

In certain embodiments of formula I, R⁴ is C₁₋₆alkoxy.

In certain embodiments of formula I, R⁴ is halo-C₁₋₆alkyl.

In certain embodiments of formula I, R⁴ is halo-C₁₋₆alkoxy.

In certain embodiments of formula I, R⁴ is halo or methoxy.

In certain embodiments of formula I, R⁴ is R⁴ is fluoro, chloro, methylor methoxy.

In certain embodiments of formula I, R⁴ is fluoro, chloro or methoxy.

In certain embodiments of formula I, R⁴ is fluoro or chloro.

In certain embodiments of formula I, R⁴ is methoxy.

In certain embodiments of formula I, R⁴ is methyl

In certain embodiments of formula I, R⁴ is chloro.

In certain embodiments of formula I, R⁴ is fluoro.

In certain embodiments of formula I, R⁴ is C₃₋₆cycloalkyloxy.

In certain embodiments of formula I, R⁵ is: oxo; C₁₋₆alkyl; or—C(O)—NR^(b)R^(c).

In certain embodiments of formula I, R⁵ is oxo.

In certain embodiments of formula I, R⁵ is C₁₋₆alkyl.

In certain embodiments of formula I, R⁵ is C₃₋₆cycloalkyl.

In certain embodiments of formula I, R⁵ is C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R⁵ is —C(O)—NR^(b)R^(c).

In certain embodiments of formula I, each R⁶ is independently:C₁₋₆alkyl. hydroxy-C₁₋₆alkyl. C₁₋₆alkoxy-C₁₋₆alkyl. heterocyclyl. oxo.or —C(O)—NR^(b)R^(c).

In certain embodiments of formula I, R⁶ is C₁₋₆alkyl.

In certain embodiments of formula I, R⁶ is C₃₋₆cycloalkyl.

In certain embodiments of formula I, R⁶ is C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R⁶ is halo.

In certain embodiments of formula I, R⁶ is halo-C₁₋₆alkyl.

In certain embodiments of formula I, R⁶ is hydroxy-C₁₋₆alkyl.

In certain embodiments of formula I, R⁶ is C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I, R⁶ is heterocyclyl.

In certain embodiments of formula I, R⁶ is oxo.

In certain embodiments of formula I, R⁶ is —C(O)—NR^(b)R^(c).

In certain embodiments of formula I, R^(b) and R^(c) together with theatoms to which they are attached form a heterocyclyl group thatoptionally includes an additional heteroatom selected from O, N and Sand which is optionally substituted one or more times with R⁶.

In certain embodiments of formula I, R^(b) and R^(c) together with theatoms to which they are attached form piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, pyrrolidinyl, azetidinyl, azepinyl,oxazepinyl or diazepinyl, each optionally substituted one or more timeswith R⁶.

In certain embodiments of formula I, R^(b) and R^(c) together with theatoms to which they are attached form piperidinyl, piperazinyl, ormorpholinyl, each optionally substituted one or more times with R⁶.

In certain embodiments of formula I, R^(b) and R^(c) together with theatoms to which they are attached form piperidinyl optionally substitutedone or more times with R⁶.

In certain embodiments of formula I, R^(b) and R^(c) together with theatoms to which they are attached form piperazinyl optionally substitutedone or more times with R⁶.

In certain embodiments of formula I, R^(b) and R^(c) together with theatoms to which they are attached form morpholinyl optionally substitutedone or more times with R⁶.

In certain embodiments of formula I, R^(b) and R^(c) together with theatoms to which they are attached form thiomorpholinyl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R^(b) and R^(c) together with theatoms to which they are attached form pyrrolidinyl optionallysubstituted one or more times with R⁶.

In certain embodiments of formula I, R^(b) and R^(c) together with theatoms to which they are attached form azetidinyl optionally substitutedone or more times with R⁶.

In certain embodiments of formula I, R^(b) and R^(c) together with theatoms to which they are attached form azepinyl optionally substitutedone or more times with R⁶.

In certain embodiments of formula I, R^(b) and R^(c) together with theatoms to which they are attached form oxazepinyl optionally substitutedone or more times with R⁶.

In certain embodiments of formula I, R^(b) and R^(c) together with theatoms to which they are attached form diazepinyl, optionally substitutedone or more times with R⁶.

In embodiments of the invention wherein R⁶ is heterocyclyl or contains aheterocyclyl moiety, such heterocyclyl may be azepinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl,pyrrolidinyl, tetrahydrofuranyl, azetidinyl or oxetanyl.

In embodiments of the invention wherein R⁶ is heterocyclyl or contains aheterocyclyl moiety, such heterocyclyl may be piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl,oxetanyl, azetidinyl, azepinyl, oxazepinyl, or pyrrolidinyl.

In embodiments of the invention wherein R⁶ is heterocyclyl or contains aheterocyclyl moiety, such heterocyclyl may be piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl.

In certain embodiments of formula I, R⁶ is oxetanyl.

In certain embodiments of the invention, the subject compounds are offormula IIa or IIb:

wherein:

m is: 0; 1 or 2;

Z is; —C(R⁷)₂—; —NR⁸— or —O—; or Z is absent;

each R⁷ is independently: hydrogen; or C₁₋₆alkyl; and

each R⁸ is independently: hydrogen; C₁₋₆alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; halo; halo-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; heterocyclyl; or —C(O)—NR^(b)R^(c); and

X, R¹, R², R³ and R⁴ are as defined herein for formula I.

In certain embodiments, the compounds are of formula IIa.

In certain embodiments, the compounds are of formula IIb.

In certain embodiments of formula IIa and IIb, when Z is absent, m is 1or 2.

In certain embodiments of formula IIa and IIb, m is 0.

In certain embodiments of formula IIa and IIb, m is 1

In certain embodiments of formula IIa and IIb, m is 2.

In certain embodiments of formula IIa and IIb, m is 0 or 1

In certain embodiments of formula IIa and IIb, m is 1 or 2.

In certain embodiments of formula IIa and IIb, Z is —C(R⁷)₂—.

In certain embodiments of formula IIa and IIb, Z is —NR⁸—.

In certain embodiments of formula IIa and IIb, Z is —O—.

In certain embodiments of formula IIa and IIb, Z is absent.

In certain embodiments of formula IIa and IIb, R⁷ is hydrogen.

In certain embodiments of formula IIa and IIb, R⁷ is C₁₋₆alkyl.

In certain embodiments of formula IIa and IIb, each R⁸ is independently:C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl; halo;halo-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; heterocyclyl;or —C(O)—NR^(b)R^(c).

In certain embodiments of formula IIa and IIb, each R⁸ is independently:C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; oxetanyl; or —C(O)—NR^(b)R^(c).

In certain embodiments of formula IIa and IIb, R⁸ is C₁₋₆alkyl.

In certain embodiments of formula IIa and IIb, R⁸ is C₃₋₆cycloalkyl.

In certain embodiments of formula IIa and IIb, R⁸ isC₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula IIa and IIb, R⁸ is halo.

In certain embodiments of formula IIa and IIb, R⁸ is halo-C₁₋₆alkyl.

In certain embodiments of formula IIa and IIb, R⁸ is hydroxy-C₁₋₆alkyl.

In certain embodiments of formula IIa and IIb, R⁸ isC₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula IIa and IIb, R⁸ is heterocyclyl.

In certain embodiments of formula IIa and IIb, R⁸ is —C(O)—NR^(b)R^(c).

In embodiments of the invention wherein R⁸ is heterocyclyl or contains aheterocyclyl moiety, such heterocyclyl may be azepinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl,pyrrolidinyl, tetrahydrofuranyl, azetidinyl or oxetanyl.

In embodiments of the invention wherein R⁸ is heterocyclyl or contains aheterocyclyl moiety, such heterocyclyl may be piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl,oxetanyl, azetidinyl, azepinyl, oxazepinyl, or pyrrolidinyl.

In embodiments of the invention wherein R⁸ is heterocyclyl or contains aheterocyclyl moiety, such heterocyclyl may be piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl.

In certain embodiments of formula I, R⁸ is oxetanyl.

In certain embodiments of the invention, the subject compounds are offormula IIIa or IIIb:

wherein:

R⁹ is: hydrogen; C₁₋₆alkyl; C₃₋₆cycloalkyl; or C₃₋₆cycloalkyl-C₁₋₆alkyl;and

X, R¹, R², R³, R^(b) and R^(c) are as defined herein for formula I.

In certain embodiments of the invention, the subject compounds are offormula IIIa.

In certain embodiments of the invention, the subject compounds are offormula IIIb.

In certain embodiments of formula IIIa and IIIb, R⁹ is: hydrogen; orC₁₋₆alkyl.

The invention also provides a method for treating a disease or conditionmediated by or otherwise associated with the LRRK2 receptor, the methodcomprising administering to a subject in need thereof an effectiveamount of a compound of the invention.

The disease may be a neurodegenerative disease such as Parkinson'sdisease, Huntington's disease or Lewie body dementia.

The disease may be a CNS disorder such as Alzheimer's disease and L-Dopainduced dyskinesia.

The disease may be a cancer or proliferative disorder such as kidney,breast, prostate, blood, papillary or lung cancer, acute myelogenousleukemia, or multiple myeloma.

The disease may be an inflammatory disease such as leprosy, Crohn'sdisease, amyotrophic lateral sclerosis, rheumatoid arthritis, andankylosing spondylytis.

The invention also provides a method for enhancing cognitive memory, themethod comprising administering to a subject in need thereof aneffective amount of a compound of the invention.

Representative compounds in accordance with the methods of the inventionare shown in the experimental examples below.

Synthesis

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 1991, Volumes 1-40. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this Application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described herein may beconducted under an inert atmosphere at atmospheric pressure at areaction temperature range of from about −78° C. to about 150° C., forexample, from about 0° C. to about 125° C., or conveniently at aboutroom (or ambient) temperature, e.g., about 20° C.

Scheme A below illustrates one synthetic procedure usable to preparespecific compounds of formula I or formula II, wherein X, m, R¹, R², R³,R⁴ and R⁵ are as defined herein.

In step 1 of Scheme A, dichloropyrimidine compound a is reacted withreagent b to afford pyrimidine compound c. The reaction of step 1 maytake place under polar solvent conditions. In embodiments of theinvention where X is —O— (i.e., reagent b is an alcohol), the reactionof step 1 may be carried out in the presence of base.

In step 2, pyrimidine compound c undergoes reaction with anilinecompound d to provide a phenylaminopyridine compound of formula I inaccordance with the invention. The reaction of step 2 may take place inpolar protic solvent and in the presence of acid such as HCl. Manyaniline compound d are commercially available or can be easily preparedfrom nitrobenzenes as shown in the Examples below.

Many variations on the procedure of Scheme A are possible and willsuggest themselves to those skilled in the art. Specific details forproducing compounds of the invention are described in the Examplesbelow.

Administration and Pharmaceutical Composition

The invention includes pharmaceutical compositions comprising at leastone compound of the present invention, or an individual isomer, racemicor non-racemic mixture of isomers or a pharmaceutically acceptable saltor solvate thereof, together with at least one pharmaceuticallyacceptable carrier, and optionally other therapeutic and/or prophylacticingredients.

In general, the compounds of the invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, for example 1-100 mg daily, andmost preferably 1-30 mg daily, depending upon numerous factors such asthe severity of the disease to be treated, the age and relative healthof the subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this Application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

Compounds of the invention may be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral(including intramuscular, intraarterial, intrathecal, subcutaneous andintravenous) administration or in a form suitable for administration byinhalation or insufflation. A particular manner of administration isgenerally oral using a convenient daily dosage regimen which can beadjusted according to the degree of affliction.

A compound or compounds of the invention, together with one or moreconventional adjuvants, carriers, or diluents, may be placed into theform of pharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the invention may be formulated in a wide variety oforal administration dosage forms. The pharmaceutical compositions anddosage forms may comprise a compound or compounds of the presentinvention or pharmaceutically acceptable salts thereof as the activecomponent. The pharmaceutically acceptable carriers may be either solidor liquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier may be one or more substances which may also act as diluents,flavouring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial. In powders, the carrier generally is a finely divided solidwhich is a mixture with the finely divided active component. In tablets,the active component generally is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired. The powders and tablets may contain from aboutone (1) to about seventy (70) percent of the active compound. Suitablecarriers include but are not limited to magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier, providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is in association with it. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges maybe as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatine andglycerine or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the invention may be formulated for administration assuppositories. A low melting wax, such as a mixture of fatty acidglycerides or cocoa butter is first melted and the active component isdispersed homogeneously, for example, by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and to solidify.

The compounds of the invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The subject compounds may be formulated for nasal administration. Thesolutions or suspensions are applied directly to the nasal cavity byconventional means, for example, with a dropper, pipette or spray. Theformulations may be provided in a single or multidose form. In thelatter case of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

The compounds of the invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatine orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations may be in unit dosage forms. In suchform, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described below.

Utility

The compounds of the invention are useful for treatment ofLRRK2-mediated diseases or conditions, including neurodegenerativediseases such as Parkinson's disease, Lewy body dementia andHuntington's disease, and for enhancemenent of cognitive memorygenerally in subjects in need thereof.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Unless otherwise stated, all temperatures including melting points(i.e., MP) are in degrees celsius (° C.). It should be appreciated thatthe reaction which produces the indicated and/or the desired product maynot necessarily result directly from the combination of two reagentswhich were initially added, i.e., there may be one or more intermediateswhich are produced in the mixture which ultimately leads to theformation of the indicated and/or the desired product. The followingabbreviations may be used in the Preparations and Examples.

LIST OF ABBREVIATIONS

-   AcOH Acetic acid-   AIBN 2,2′-Azobis(2-methylpropionitrile)-   Atm. Atmosphere-   (BOC)₂O di-tert-Butyl dicarbonate-   DavePhos 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl-   DCM Dichloromethane/Methylene chloride-   DIAD Diisopropyl azodicarboxylate-   DIPEA Diisopropylethylamine-   DMAP 4-Dimethylaminopyridine-   DME 1,2-Dimethoxyethane-   DMF N,N-Dimethylformamide-   DMSO Dimethyl sulfoxide-   DPPF 1,1′-Bis(diphenylphosphino)ferrocene-   Et₂O Diethyl ether-   EtOH Ethanol/Ethyl alcohol-   EtOAc Ethyl acetate-   HATU 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium    hexafluorophosphate Methanaminium-   HBTU O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBT 1-Hydroxybenzotriazole-   HPLC High pressure liquid chromatography-   RP HPLC Reverse phase high pressure liquid chromatography-   i-PrOH Isopropanol/isopropyl alcohol-   LCMS Liquid Chromatograph/Mass Spectroscopy-   MeOH Methanol/Methyl alcohol-   MW Microwaves-   NBS N-Bromosuccinimide-   NMP 1-Methyl-2-pyrrolidinone-   PSI Pound per square inch-   RT Room temperature-   TBDMS tert-Butyldimethylsilyl-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   TLC Thin layer chromatography

Preparation 1 2-chloro-5-fluoro-N-methylpyrimidin-4-amine

To a 250 mL round bottom flask equipped with a stir bar was added 9.0 g5-fluoro-2,4-dichloro-pyrimidine, 40 mL methanol and 15 mL of 8Mmethylamine in ethanol. The reaction heated up (mild exo-therm) and wasallowed to stir at room temperature for ˜30 minutes. A check by TLC (1:1EtOAc:heptane) and LCMS showed complete reaction. The reaction wasconcentrated down to give 9.77 g crude material which was purified on asilica column running a gradient of 1% to 10% MeOH in DCM over 35minutes to give 6.77 g pure 2-chloro-5-fluoro-N-methylpyrimidin-4-amine.

The same method was used to make the compounds shown in Table 1 below,using the appropriate commercially available substituted2,4-dichloro-pyrimidines and amines.

TABLE 1  1 2-chloro-5-chloro-N- methylpyrimidin-4- amine

 2 2-chloro-5-bromo-N- methylpyrimidin-4- amine

 3 2-chloro-5-trifluoromethyl-N- methylpyrimidin-4-amine

 6 2-chloro-5-methoxy-N- methylpyrimidin-4- amine

 8 2-chloro-5-fluoro-N,N- dimethylpyrimidin- 4-amine

 9 2-chloro-5-chloro-N- ethylpyrimidin-4- amine

10 2-chloro-5-chloro-N- propylpyrimidin-4- amine

11 2-chloro-5-chloro-N- isopropylpyrimidin-4- amine

12 2-chloro-5-chloro-N- isobutylpyrimidin-4- amine

13 4-(2,5-dichloropyrimidin- 4-yl)morpholine

14 2,5-dichloropyrimidin- 4-amine

15 2,5-dichloro-N,N- dimethylpyrimidin-4- amine

16 4-(azetidin-1-yl)-2,5- dichloropyrimidine

17 2,5-dichloro-4- (pyrrolidin-1-yl)pyrimidine

18 2,5-dichloro-4- (piperidin-1-yl)pyrimidine

19 2,5-dichloro-4-(2- (methoxymethyl) piperidin-1-yl)pyrimidine

20 2,5-dichloro-4-(4- (methoxymethyl) piperidin-1-yl)pyrimidine

21 2,5-dichloro-N- (cyclopropylmethyl) pyrimidin-4-amine

22 2,5-dichloro-N- (cyclobutylmethyl) pyrimidin-4-amine

23 2,5-dichloro-N- (cyclopentylmethyl) pyrimidin-4-amine

24 2-chloro-N- methylpyrimidin-4-amine

25 2,5-dichloro-N- (2-methoxyethyl)pyrimidin- 4-amine

Preparation 2 2,5-dichloro-4-methoxypyrimidine

To a 250 mL round bottom flask equipped with a stir bar was added 1 g5-chloro-2,4-dichloro-pyrimidine, and 15 mL of diethyl ether. Themixture was cooled to 0° C. in an ice bath and then 1 equivalent ofsodium methoxide in methanol (prepared from reacting 120 mg of sodiumwith 4 mL of methanol at room temperature) was slowly added. Thereaction was stirred over night at room temperature and checked by LCMS.The white precipitate was filtered and the solid washed with coldmethanol. After drying, 0.98 g of pure 2,5-dichloro-4-methoxypyrimidinewas obtained and this material was used without further purification.

The same method was used to make the compounds shown in Table 2 below,using the appropriate commercially available alcohols and theappropriately substituted 2,4-dichloro-pyrimidines.

TABLE 2 1 2,5-dichloro-4-ethoxypyrimidine

2 2,5-dichloro-4-propoxypyrimidine

3 2,5-dichloro-4-isoprpoxypyrimidine

6 5-bromo-2-chloro-4- methoxypyrimidine

7 2-chloro-5-iodo-4- methoxypyrimidine

Preparation 3 5-Amino-6-methoxy-2-methylisoindolin-1-one Step 1:5-Methoxy-2-methyl-4-nitrobenzonitrile

To 5-methoxy-2-methyl-4-nitroaniline (4.9 g, 26.8 mmol) in a mixture ofacetone (17.5 mL) and water (19 mL) at 0° C. was added conc. HCl (5.6mL). A solution of sodium nitrite (2.25 g, 32.6 mmol) in water (7.5 mL)was added dropwise and the mixture was allowed to stir at 0° C. for 30min. The mixture was then added dropwise to a mixture of copper cyanide(3.75 g, 42 mmol) and sodium cyanide (5.5 g, 112 mmol) in water (25 mL)and EtOAc (12.5 mL). The mixture was allowed to stir at RT for 2 h andthen water (50 mL) was added. The mixture was extracted with EtOAc(3×100 mL) and the combined organic fractions were washed with 2 MNaOH(aq) (50 mL) and brine (50 mL). The organic fraction was passedthrough a hydrophobic frit and the solvent was removed in vacuo. Theresidue was triturated with iso-hexane and dried to give5-methoxy-2-methyl-4-nitrobenzonitrile (4.62 g, 90%) as an off-whitesolid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M]⁻=192 at 3.19 min. ¹H NMR (400MHz, CDCl₃): δ 7.72 (s, 1H), 7.31 (s, 1H), 3.98 (s, 3H), 2.55 (s, 3H).

Step 2: 5-Methoxy-2-methyl-4-nitrobenzoic acid

A mixture of 5-methoxy-2-methyl-4-nitrobenzonitrile (2 g, 10.4 mmol) inAcOH (20 mL), water (20 mL) and conc. sulphuric acid (20 mL) was heatedto 120° C. for 5 h. Water (100 mL) and DCM (100 mL) were added and themixture was passed through a hydrophobic frit. The solvent was removedin vacuo to give 5-methoxy-2-methyl-4-nitrobenzoic acid (1.27 g, 58%) asan off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M−H]⁻=210 at 3.37min. ¹H NMR (400 MHz, CDCl₃): δ 7.75 (s, 1H), 7.70 (s, 1H), 3.99 (s,3H), 2.62 (s, 3H).

Step 3: Methyl 5-methoxy-2-methyl-4-nitrobenzoate

To 5-methoxy-2-methyl-4-nitrobenzoic acid (1.27 g, 6 mmol) in methanol(15 mL) was added thionyl chloride (0.44 mL, 6 mmol) dropwise. Themixture was heated to reflux for 3 h and then allowed to cool. Thesolvent was removed in vacuo and the residue was partitioned between DCM(20 mL) and saturated aqueous NaHCO₃ (20 mL). The organic phase waspassed through a hydrophobic frit and the solvent was removed in vacuo.Purification of the residue via silica gel column chromatography (0-100%EtOAc in iso-hexane) gave methyl 5-methoxy-2-methyl-4-nitrobenzoate(1.11 g, 82%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN):[M+H]⁺=226 at 3.92 min. ¹H NMR (400 MHz, CDCl₃): δ 7.68 (s, 1H), 7.60(s, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 2.55 (s, 3H).

Step 4: Methyl 2-(bromomethyl)-5-methoxy-4-nitrobenzoate

A mixture of methyl 5-methoxy-2-methyl-4-nitrobenzoate (1.11 g, 5 mmol)and NBS (1.07 g, 6 mmol) in MeCN (20 mL) was degassed and then AIBN (18mg, 0.11 mmol) was added. The mixture was heated to 70° C. for 18 h. DCM(50 mL) and water (50 mL) were added and the organic phase was passedthrough a hydrophobic frit. The solvent was removed in vacuo andpurification of the residue via silica gel column chromatography (0-100%EtOAc in iso-hexane) in order to remove baseline impurities gave methyl2-(bromomethyl)-5-methoxy-4-nitrobenzoate (477 mg, 31%) as an off-whitesolid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M−Br]⁻=224 at 3.92 min. ¹H NMR(400 MHz, CDCl₃): δ 7.92 (s, 1H), 7.66 (s, 1H), 4.88 (s, 2H), 4.02 (s,3H), 4.00 (s, 3H).

Step 5: 6-Methoxy-2-methyl-5-nitroisoindolin-1-one

To methyl 2-(bromomethyl)-5-methoxy-4-nitrobenzoate (212 mg, 0.7 mmol)in methanol (6 mL) was added Et₃N (0.12 mL, 0.84 mmol) and methylaminein EtOH (0.11 mL, ˜8 M in EtOH, 0.84 mmol). The mixture was heated to70° C. for 5 h. and then EtOAc (30 mL) and 2M HCl_((aq)) (30 mL) wasadded. The layers were separated and the aqueous layer was extractedwith EtOAc (2×30 mL). The combined organic fractions were passed througha hydrophobic frit and the solvent was removed in vacuo. Purification ofthe residue via silica gel column chromatography (0-100% EtOAc iniso-hexane then EtOAc-10% MeOH in DCM) gave6-methoxy-2-methyl-5-nitroisoindolin-1-one (117 mg, 75%) as an off-whitesolid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]⁺=223 at 3.02 min. ¹H NMR(400 MHz, CDCl₃): δ 7.86 (s, 1H), 7.53 (s, 1H), 4.40 (s, 2H), 4.02 (s,3H), 3.24 (s, 3H).

Step 6: 5-Amino-6-methoxy-2-methylisoindolin-1-one

To 6-methoxy-2-methyl-5-nitroisoindolin-1-one (111 mg, 0.5 mmol) inethanol (6 mL) and water (0.6 mL) was added SnCl₂.2H₂O (451 mg, 2 mmol)and the mixture was heated to 65° C. for 5 h. DCM (20 mL) and 2MNaOH_((aq)) (10 mL) were added and the mixture was passed through ahydrophobic frit. The solvent was removed in vacuo to give5-amino-6-methoxy-2-methylisoindolin-1-one (68 mg, 71%) as an off-whitesolid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]⁺=193 at 2.32 min. ¹H NMR(400 MHz, DMSO): δ 7.01 (s, 1H), 6.74 (s, 1H), 5.44 (br s, 2H), 4.24 (s,2H), 3.85 (s, 3H), 3.02 (s, 3H).

Preparation 4 6-Amino-5-methoxy-2-methylisoindolin-1-one Step 1:2-Methyl-4,5-dinitrobenzoic acid

To concentrated sulfuric acid (10 mL) at 0° C. was added concentratednitric acid (10 mL) dropwise and the mixture was allowed to stir at 0°C. for 10 min. 2-Methyl-4-nitrobenzic acid (1.81 g, 10 mmol) was addedand the mixture was allowed to stir at RT for 5 d. The mixture waspoured into ice-cold water and the solid was removed by filtration anddried to give 2-methyl-4,5-dinitrobenzoic acid (1.93 g, 85%) as anoff-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M−H]⁻=225 at 3.10 min.¹H NMR (400 MHz, d6-DMSO): δ 8.53 (s, 1H), 8.26 (s, 1H), 2.71 (s, 3H).

Step 2: 4-Methoxy-2-methyl-5-nitrobenzoic acid

2-Methyl-4,5-dinitrobenzoic acid (1.93 g, 8.5 mmol) was added to KOH(2.38 g, 42.5 mmol) in methanol (50 mL) and the mixture was heated to70° C. for 1.5 h. The mixture was acidified with 2 M HCl_((aq)) and thesolid was removed by filtration and dried to give4-methoxy-2-methyl-5-nitrobenzoic acid (1.08 g, 60%) as an off-whitesolid. LCMS (10 cm_ESCI_Formic_MeCN): [M−H]⁻=210 at 3.23 min. ¹H NMR(400 MHz, d6-DMSO): δ 8.40 (s, 1H), 7.36 (s, 1H), 4.02 (s, 3H), 2.67 (s,3H).

Step 3: Methyl 4-methoxy-2-methyl-5-nitrobenzoate

To 4-methoxy-2-methyl-5-nitrobenzoic acid (1.06 g, 5 mmol) in methanol(10 mL) was added thionyl chloride (0.36 mL, 5 mmol) dropwise. Themixture was heated to reflux for 5 h and then allowed to cool. Thesolvent was removed in vacuo and the residue was partitioned between DCM(20 mL) and saturated aqueous NaHCO₃ (20 mL). The organic phase waspassed through a hydrophobic frit and the solvent was removed in vacuoto give methyl 4-methoxy-2-methyl-5-nitrobenzoate (998 mg, 89%) as anoff-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]⁺=226 at 3.25 min.¹H NMR (400 MHz, CDCl₃): δ 8.56 (s, 1H), 6.91 (s, 1H), 4.01 (s, 3H),3.90 (s, 3H), 2.71 (s, 3H).

Step 4: Methyl 2-(bromomethyl)-4-methoxy-5-nitrobenzoate

A mixture of methyl 4-methoxy-2-methyl-5-nitrobenzoate (994 mg, 4.41mmol) and NBS (943 mg, 5.3 mmol) in MeCN (20 mL) was degassed and thenAIBN (15 mg, 0.09 mmol) was added. The mixture was heated to 70° C. for18 h. Further AIBN (15 mg, 0.09 mmol) was added and the mixture washeated to 70° C. for 24 h. Further AIBN (15 mg, 0.09 mmol) and NBS (300mg, 1.7 mmol) were added and the mixture heated to 70° C. for 24 h.Further AIBN (15 mg, 0.09 mmol) was added and the mixture was heated to70° C. for 24 h. DCM (50 mL) and water (50 mL) were added and theorganic phase was passed through a hydrophobic frit. The solvent wasremoved in vacuo to give crude methyl2-(bromomethyl)-4-methoxy-5-nitrobenzoate that was used directly in thenext reaction without any purification.

Step 5: 5-Methoxy-2-methyl-6-nitroisoindolin-1-one

To crude 2-(bromomethyl)-4-methoxy-5-nitrobenzoate (<4 mmol) in methanol(36 mL) was added Et₃N (0.68 mL, 4.8 mmol) and methylamine in EtOH (0.6mL, ˜8 M in EtOH, 4.8 mmol). The mixture was heated to 70° C. for 5 h.and then EtOAc (30 mL) and 2M HCl_((aq)) (30 mL) was added. The layerswere separated and the aqueous layer was extracted with EtOAc (2×30 mL).The combined organic fractions were passed through a hydrophobic fritand the solvent was removed in vacuo. Purification of the residue viasilica gel column chromatography (0-100% EtOAc in iso-hexane thenEtOAc-10% MeOH in DCM) gave impure5-methoxy-2-methyl-6-nitroisoindolin-1-one (487 mg) as a brown solid.The crude material was used directly in the next reaction without anyfurther purification.

Step 6: 6-Amino-5-methoxy-2-methylisoindolin-1-one

To crude 5-methoxy-2-methyl-6-nitroisoindolin-1-one (121 mg, 0.54 mmol)in ethanol (6 mL) and water (0.6 mL) was added SnCl₂.2H₂O (487 mg, 2.16mmol) and the mixture was heated to 65° C. for 24 h. DCM (10 mL) and 2MNaOH_((aq)) (10 mL) were added and the mixture was passed through ahydrophobic frit. The solvent was removed in vacuo to give impure6-amino-5-methoxy-2-methylisoindolin-1-one (101 mg, 97%) as an off-whitesolid. The crude material was used directly in the next reaction withoutany further purification. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]⁺=193 at2.00 min.

Preparation 5 5-Amino-6-chloro-2-methylisoindolin-1-one Step 1:5-Chloro-2-methyl-4-nitrobenzonitrile

To 5-chloro-2-methyl-4-nitroaniline (5 g, 26.8 mmol) in a mixture ofacetone (17.5 mL) and water (19 mL) at 0° C. was added conc. HCl (5.6mL). A solution of sodium nitrite (2.25 g, 32.6 mmol) in water (7.5 mL)was added dropwise and the mixture was allowed to stir at 0° C. for 30min. The mixture was then added dropwise to a mixture of copper cyanide(3.75 g, 42 mmol) and sodium cyanide (5.5 g, 112 mmol) in water (25 mL)and EtOAc (12.5 mL). The mixture was allowed to stir at RT for 1 h andthen water (50 mL) was added. The mixture was extracted with EtOAc(3×100 mL) and the combined organic fractions were washed with 2 MNaOH(aq) (50 mL) and brine (50 mL). The organic fraction was passedthrough a hydrophobic frit and the solvent was removed in vacuo. Theresidue was suspended in a 1:1 mixture of diethyl ether:iso-hexane. Thesolid formed was removed by filtration and washed with iso-hexane anddried. Further fractions were isolated from the filtrate and combinedwith the initial solid fraction to give5-chloro-2-methyl-4-nitrobenzonitrile (3.22 g, 61%) as an off-whitesolid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]⁺=197 at 3.97 min. ¹H NMR(400 MHz, CDCl₃): δ 7.80 (s, 1H), 7.80 (s, 1H), 2.63 (s, 3H).

Step 2: 4-Amino-5-chloro-2-methylbenzonitrile

To 5-chloro-2-methyl-4-nitrobenzonitrile (192 mg, 1 mmol) in ethanol (6mL) and water (0.6 mL) was added SnCl₂.2H₂O (903 mg, 4 mmol) and themixture was heated to 65° C. for 5 h. DCM (10 mL) and 2M NaOH(aq) (10mL) were added, and the mixture was passed through a hydrophobic frit.The solvent was removed in vacuo to give4-amino-5-chloro-2-methylbenzonitrile (131 mg, 81%) as an off-whitesolid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]⁺=163 at 3.37 min. ¹H NMR(400 MHz, CDCl₃): δ 6.89 (s, 1H), 6.52 (s, 1H), 4.21 (br s, 2H), 3.84(s, 3H), 2.38 (s, 3H).

Step 3: 5-Chloro-2-methyl-4-nitrobenzonitrile

A mixture of 5-chloro-2-methyl-4-nitrobenzonitrile (1 g, 5 mmol) in AcOH(10 mL), water (10 mL) and conc. sulphuric acid (10 mL) was heated to120° C. for 5 h. Water (100 mL) was added and the solid was removed byfiltration and dried to give 5-chloro-2-methyl-4-nitrobenzoic acid (905mg, 84%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN):[M−H]⁻=214 at 2.12 min. ¹H NMR (400 MHz, CDCl₃): δ 8.22 (s, 1H), 7.76(s, 1H), 2.70 (s, 3H).

Step 4: Methyl 5-chloro-2-methyl-4-nitrobenzoate

To 5-chloro-2-methyl-4-nitrobenzoic acid (900 mg, 4.15 mmol) in methanol(10 mL) was added thionyl chloride (0.3 mL, 4.15 mmol) dropwise. Themixture was heated to reflux for 5 h and then allowed to cool. Thesolvent was removed in vacuo and the residue was partitioned between DCM(20 mL) and saturated aqueous NaHCO₃ (20 mL). The organic phase waspassed through a hydrophobic frit and the solvent was removed in vacuoto give methyl 5-chloro-2-methyl-4-nitrobenzoate (880 mg, 92%) as anoff-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]⁺=230 at 4.25 min.¹H NMR (400 MHz, CDCl₃): δ 8.08 (s, 1H), 7.73 (s, 1H), 3.95 (s, 3H),2.64 (s, 3H).

Step 5: Methyl 2-(bromomethyl)-5-chloro-4-nitrobenzoate

A mixture of methyl 5-chloro-2-methyl-4-nitrobenzoate (862 mg, 4 mmol)and NBS (854 mg, 4.8 mmol) in MeCN (16 mL) was degassed and then AIBN(14 mg, 0.08 mmol) was added. The mixture was heated to 70° C. for 18 h.The solvent was removed in vacuo and the residue was partitioned betweenDCM (50 mL) and water (50 mL). The organic phase was passed through ahydrophobic frit and the solvent was removed in vacuo. Purification ofthe residue via silica gel column chromatography (0-100% EtOAc iniso-hexane) in order to remove baseline impurities gave methyl2-(bromomethyl)-5-chloro-4-nitrobenzoate (1.09 g, 89%) as a brown oil.¹H NMR (400 MHz, CDCl₃): δ 8.14 (s, 1H), 7.98 (s, 1H), 4.91 (s, 2H),4.00 (s, 3H).

Step 6: 6-Chloro-2-methyl-5-nitroisoindolin-1-one

To methyl 2-(bromomethyl)-5-chloro-4-nitrobenzoate (617 mg, 2 mmol) inmethanol (18 mL) was added Et₃N (0.34 mL, 2.4 mmol) and methylamine inEtOH (0.3 mL, ˜d 8 M in EtOH, 2.4 mmol). The mixture was heated to 70°C. for 3 h. and then EtOAc (30 mL) and 2M HCl_((aq)) (30 mL) was added.The layers were separated and the aqueous layer was extracted with EtOAc(2×30 mL). The combined organic fractions were passed through ahydrophobic frit and the solvent was removed in vacuo. Purification ofthe residue via silica gel column chromatography (0-10% methanol in DCM)gave 6-chloro-2-methyl-5-nitroisoindolin-1-one (347 mg, 77%) as anoff-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]⁺=227 at 2.89 min.¹H NMR (400 MHz, CDCl₃): δ 8.00 (s, 1H), 7.90 (s, 1H), 4.46 (s, 2H),3.24 (s, 3H).

Step 7: 5-Amino-6-chloro-2-methylisoindolin-1-one

To 6-chloro-2-methyl-5-nitroisoindolin-1-one (340 mg, 1.5 mmol) inethanol (9 mL) and water (0.9 mL) was added SnCl₂.2H₂O (1.35 g, 6 mmol)and the mixture was heated to 65° C. for 5 h. DCM (20 mL) and 2MNaOH(aq) (10 mL) were added and the mixture was passed through ahydrophobic frit. The solvent was removed in vacuo to give5-amino-6-chloro-2-methylisoindolin-1-one (251 mg, 85%) as an off-whitesolid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=197 at 2.31 min. ¹H NMR(400 MHz, d6-DMSO): δ 7.45 (s, 1H), 6.90 (s, 1H), 5.99 (br s, 2H), 4.32(s, 2H), 3.01 (s, 3H).

Preparation 6 5-Amino-4-methoxy-2-methylisoindolin-1-one Step 1:3-Hydroxy-2-methyl-4-nitrobenzoic acid

To a solution of 3-hydroxy-2-methylbenzoic acid (5.00 g, 25.3 mmol) inconcentrated H₂SO₄ (98%, 10 mL) was added concentrated HNO₃ (63%, 10 mL)dropwise. The mixture was stirred at −40° C. for 10 min. The mixture waspoured into ice-water and extracted by EA (3 times). The organic layerswere combined, dried over anhydrous Na₂SO₄. Then the solvent wasevaporated in vacuo to afford 3-hydroxy-2-methyl-4-nitrobenzoic acid asa yellow solid, which was used for next step without furtherpurification.

Step 2: Methyl 3-methoxy-2-methyl-4-nitrobenzoate

To a solution of the crude 3-hydroxy-2-methyl-4-nitrobenzoic acid inacetone (300 mL) was added K₂CO₃ (15.8 g, 115 mmol) and Me₂SO₄ (8.7 g,69 mmol). The mixture was refluxed at 60° C. for 2 h. After the solventwas evaporated in vacuo, the resulting residue was purified by silicagel-column (eluting with PE/EA=10:1) to afford methyl3-methoxy-2-methyl-4-nitrobenzoate as a yellowish solid (2.7 g, 33%yield, two steps). m/z (ES+APCI)⁺: [M+H]⁺226.1.

Step 3: Methyl 2-(bromomethyl)-3-methoxy-4-nitrobenzoate

To a solution of methyl 3-methoxy-2-methyl-4-nitrobenzoate (800 mg, 3.6mmol) in CH₃CN (10 mL) was added NBS (770 mg, 4.3 mmol) and AIBN (12 mg,0.072 mmol) under the protection of N₂. The mixture was refluxed at 80°C. for overnight. After the solvent was evaporated in vacuo, theresulting residue was purified by silica gel-column (eluting withPE/EA=15:1) to afford methyl 2-(bromomethyl)-3-methoxy-4-nitrobenzoateas yellow oil (910 mg, yield 84%). m/z (ES+APCI)⁺: [M−Br]⁺224.1.

Step 4: 4-Methoxy-2-methyl-5-nitroisoindolin-1-one

To a solution of methyl 2-(bromomethyl)-3-methoxy-4-nitrobenzoate (300mg, 1.0 mmol) in MeOH (10 mL) was added Et₃N (120 mg, 1.2 mmol) andCH₃NH₂ (1.0 mL, 4M in MeOH). The solution was stirred at 70° C. for 4 h.The solvent was evaporated in vacuo, and the residue was purified bysilica gel-column (eluting with PE/EA=10:1) to afford4-methoxy-2-methyl-5-nitroisoindolin-1-one as a yellow solid (110 mg,yield 50%). m/z (ES+APCI)⁺: [M+H]⁺223.1.

Step 5: 5-Amino-4-methoxy-2-methylisoindolin-1-one

To a solution of 4-methoxy-2-methyl-5-nitroisoindolin-1-one (155 mg, 0.7mmol) in MeOH (10 mL) was added Pd/C (60 mg). The mixture was stirred at50° C. under H₂ for 6 h. The resulting suspension was filtered. Thefiltrate was concentrated under reduced pressure to afford5-amino-4-methoxy-2-methylisoindolin-1-one (70 mg, yield 52%). m/z(ES+APCI)⁺: [M+H]⁺193.1.

Example 17-Chloro-4-methyl-8-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-oneStep 1: 2-((tert-Butyldimethylsilyl)oxy)-N-methylethanamine

A solution of tert-butyldimethylchlorosilane (4.2 g, 27.9 mmol) indichloromethane (10 mL) was added dropwise over 3 min to a stirredsolution of 2-(methylamino)ethanol (2.0 g, 26.6 mmol) and imidazole indichloromethane (20 mL) at room temperature. The resulting mixture wasstirred at room temperature for 1 h. Water (20 mL) was added and thephases were separated. The aqueous phase was extracted withdichloromethane then the combined organic phases were passed through aphase separation cartridge and the solvent removed under reducedpressure to afford a colorless oil (5.10 g, 95%). This was taken throughto the next step with no further purification.

Step 2:4-Amino-N-2-tert-butyldimethylsilyl)oxy)ethyl)-5-chloro-2-methoxy-N-methylbenzamide

4-Amino-5-chloro-2-methoxybenzoic acid (3.0 g, 14.9 mmol), DIPEA (3.84g, 29.8 mmol) and HATU (6.80 g, 17.9 mmol) were stirred at roomtemperature for 20 min in dichloromethane (180 mL).2-((Tert-butyldimethylsilyl)oxy)-N-methylethanamine (3.12 g, 16.4 mmol)was added, then the reaction was stirred for 1 h after which timeanalysis by LCMS indicated the reaction was complete. Thedichloromethane was removed and the resulting residue partitionedbetween ethyl acetate and water. The layers were separated and theaqueous phase extracted with ethyl acetate. The combined organicextracts were concentrated and the resulting residue was triturated withethyl acetate-petroleum ether (1:1). The solid was collected byfiltration and discarded. The supernatant was retained and concentratedto afford a crude product that was used directly in the next step (2.0g, 36%).

Step 3: 4-Amino-5-chloro-2-hydroxy-N-(2-hydroxyethyl)-N-methylbenzamide

4-Amino-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-chloro-2-methoxy-N-methylbenzamide(2.0 g, 5.3 mmol) was stirred in dichloromethane (100 mL) at −10° C.under an atmosphere of nitrogen and a 1M solution of boron trichloridein dichloromethane (10.68 mL, 10.7 mmol) was added dropwise. Thereaction was allowed to warm to room temperature then left to stir atthis temperature for 18 h. The reaction was cooled to −10° C. and afurther 1 equivalent of boron trichloride solution was added dropwise,then the reaction was allowed to warm to room temperature and stirredfor 3 h. After this time analysis by LCMS indicated that the reactionwas complete. The reaction was cooled in a ice bath and methanol (20 mL)was added drop-wise to the reaction followed by 7N methanolic ammoniasolution (17 mL) and then a further portion of MeOH (˜80 mL) until allthe solids had dissolved. The solution was stirred for 1 h at roomtemperature then concentrated. The resulting residue was stirred withsaturated aqueous NaHCO₃ (150 mL) for 30 min then the aqueous phase wasextracted with ethyl acetate. The combined extracts were washed withbrine then passed through a phase separation cartridge and the solventwas removed under reduced pressure to afford a green gum (1.00 g, 77%).This material was taken through to the next step with no furtherpurification.

Step 4:8-Amino-7-chloro-4-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one

4-Amino-5-chloro-2-hydroxy-N-(2-hydroxyethyl)-N-methylbenzamide (300 mg,1.22 mmol) was stirred in dichloromethane at 0° C. under an atmosphereof nitrogen then TEA (247 mg, 2.4 mmol), triphenylphosphine (320 mg, 1.2mmol) and DEAD (212 mg, 1.2 mmol) were added. The reaction was allowedto stir for 1 h at 0° C., after which time LCMS indicated the formationof a peak consistent with the target material. The volatiles wereremoved under reduced pressure and the resulting gum was dissolved indichloromethane then passed through a SCX-2 20 g cartridge. Thecartridge was washed with dichloromethane-methanol 10% and the fractionswere collected in 100 mL flasks. TLC indicated that the fractions werenot identical in composition which was verified by LCMS. The purestfraction was concentrated to afford the target material (18 mg, 5%).

Step 5:7-Chloro-4-methyl-8-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one

A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.5g, 2.36 mmol),8-amino-7-chloro-4-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(0.38 mmol) and p-toluene sulphonic acid (0.49 g, 2.6 mmol) in dioxane(10 mL) was heated at 100° C. for 2 h. The mixture was cooled, filteredand the solid washed with dioxane. The solid was dried in a vacuum ovenand purified via silica gel column chromatography (20-100% ethylacetate/isohexane) gave7-chloro-4-methyl-8-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-oneas a white solid (10 mg, 28%). LCMS (10 cm_ESCI_Formic_MeCN): [MH⁺]=402at 3.04 min. ¹H NMR δ (ppm)(400 MHz, CDCl3): 8.41 (1H, s), 8.22 (1H, s),7.97 (1H, s), 7.77-7.67 (1H, m), 5.29 (1H, s), 4.47-4.39 (2H, m),3.61-3.51 (2H, m), 3.21-3.18 (3H, m), 3.20-3.07 (3H, m).

Example 27-((5-Chloro-4-(methylamino)pyrimidin-2-yl)amino)-6-methoxy-2,2,4-trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-oneStep 1: 6-Chloro-2,2-dimethyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one

To a suspension of anhydrous potassium fluoride (4.71 g, 81 mmol) in DMF(40 mL) was added 2-amino-5-nitrophenol (5.00 g, 26.5 mmol) and themixture was stirred at room temperature for 1 h. To the suspension wasadded a solution of ethyl-α-bromoisobutyrate (6.33 g, 32.5 mmol) in DMF(10 mL) dropwise over a period of 20 min. The mixture was stirred at 60°C. for 20 h. The reaction was allowed to cool, then water (150 mL) wasadded then the aqueous was extracted with ethyl acetate. The combinedorganic extracts were washed successively with 2M aqueous HCl (100 mL),water (100 mL) and brine (100 mL) then passed through a phase separationcartridge. The solvent was removed under reduced pressure and theresulting residue was suspended in ethyl acetate. The precipitate wascollected by filtration and washed with ethyl acetate to afford a paleyellow solid (2.29 g, 34%) which was taken through to the next step withno further purification.

Step 2:6-Chloro-2,2,4-trimethyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one

6-Chloro-2,2-dimethyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (2.29 g,8.9 mmol) was stirred in DMF at 0° C. under an atmosphere of nitrogenthen sodium hydride (60% dispersion in oil) (392 mg, 9.79 mmol) wasadded. The reaction was allowed to stir at room temperature for 30 minthen iodomethane (1.89 g, 13.4 mmol) was added and the reaction wasstirred at room temperature for 18 h. Analysis by LCMS indicated thatthe reaction was complete. Water (10 mL) was added carefully then theDMF was removed under reduced pressure. The residue was partitionedbetween ethyl acetate and water. The layers were separated and theaqueous phase was extracted with ethyl acetate. The organic portionswere combined then passed through a phase separation cartridge. Thesolvents were evaporated to afford an orange solid (2.4 g, quant.) whichwas taken through to the next step with no further purification.

Step 3:6-Methoxy-2,2,4-trimethyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one

Toluene-methanol (4:1) (50 mL) was degassed, then cesium carbonate (2.85g, 7.4 ml) was added followed byrac-2-(di-tert-butylphosphine)1,1′-binaphthyl (44 mg, 0.11 mmol) and6-chloro-2,2-dimethyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (1.0 g,3.7 mmol) with stirring under an atmosphere of nitrogen. Palladium (II)acetate (20 mg, 0.074 mmol) was added then the reaction was heated to75° C. for 18 h with stirring under nitrogen. The reaction was allowedto cool, then a further aliquot of palladium (II) acetate were added andthe reaction heated at 75° C. for 18 h to complete the conversion. Thereaction was allowed to cool, water (100 mL) was added then the wholewas extracted with ethyl acetate. The combined organic extracts werewashed with brine, passed through a phase separation cartridge andevaporated to afford a brown solid (˜800 mg). Purification via silicagel column chromatography (0-100% ethyl acetate/isohexane) gave6-methoxy-2,2,4-trimethyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.47g, 48%).

Step 4:7-Amino-6-methoxy-2,2,4-trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one

6-Methoxy-2,2,4-trimethyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (250mg, 0.94 mmol) was stirred in ethanol (15 mL) then tin (II) chloride wasadded. The reaction was heated to 80° C. with stirring for 2 h. Thevolatiles were removed under reduced pressure and the residue wasslurried with 2M sodium hydroxide aqueous solution. The aqueous wasextracted with ethyl acetate and the combined organic extracts werepassed through a phase separation cartridge and evaporated, to afford abrown crystalline solid (220 mg, 99%) which was taken through to thenext step with no further purification.

Step 5:7-((5-Chloro-4-(methylamino)pyrimidin-2-yl)amino)-6-methoxy-2,2,4-trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one

A mixture of 2,5-dichloro-N-methylpyrimidin-4-amine (1 mmol),7-amino-6-methoxy-2,2,4-trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (222mg, 0.94 mmol), cesium carbonate (0.65 g, 2 mmol), XantPhos (17 mg, 0.03mmol) and Pd2(dba)3 (5 mg, 0.02 mmol) in dioxane (3 mL) was sonnicatedin an ultrasonic bath for 1 min. The mixture was then degassed under astream of nitrogen for 5 min. The tube was sealed and the reaction washeated at 100° C. for 18 h. The reaction mixture was cooled and dilutedwith ethyl acetate (15 mL). The organic layer was washed with water andthe combined aqueous extracts were further washed with ethyl acetate.The combined organics were passed through a phase separation cartridgeand the solvent removed under reduced pressure. Purification of theresidue via silica gel column chromatography (0-100% ethylacetate/isohexane) gave7-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-6-methoxy-2,2,4-trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one(30 mg, 15%). LCMS (10 cm_ESCI_Formic_MeCN): [MH⁺]=378 at 2.77 min. ¹HNMR δ (ppm)(400 MHz, d6-DMSO): 8.05 (1H, s), 7.98 (1H, s), 7.54 (1H, s),7.28 (1H, d, J=5.2), 6.85 (1H, s), 3.93 (3H, s), 3.66 (3H, s), 2.91 (3H,d, J=4.6), 1.41 (6H, s).

Example 35-Methoxy-N,N-dimethyl-6-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzofuran-2-carboxamideStep 1: Methyl 5-methoxybenzofuran-2-carboxylate

2-Hydroxy-5-methoxy-benzaldehyde (10 g, 65.8 mmol) was stirred in DMF(90 mL) with potassium carbonate (23 g, 0.17 mol) under nitrogen, thenmethyl bromoacetate was added dropwise. The mixture was stirred at roomtemperature for 4 h. The reaction was then heated to 80° C. for 18 h.The reaction was allowed to cool then poured onto ice water (200 mL) andthe resulting brown suspension was allowed to stir for 30 min. Afterthis time the solid was collected by filtration and washed with water.The solid was dried to afford (5.22 g, 39%), which was taken through tothe next step with no further purification.

Step 2: Methyl 4-chloro-5-methoxybenzofuran-2-carboxylate

Methyl 5-methoxybenzofuran-2-carboxylate (5.22 g, 25.3 mmol) wasdissolved in dichloromethane, and sulfuryl chloride (3.76 g, 27.9 mmol)was added at such rate to maintain a temperature of 20° C. Afterstirring for 5 h the solution was dripped slowly onto ice water (70 mL).The organic phase was then washed with water, aqueous saturated NaHCO₃and again with water. The layers were separated and the organic portionwas passed through a phase separation cartridge and evaporated to afforda solid (5.81 g), which was taken through to the next step with nofurther purification.

Step 3: Methyl 4-chloro-5-methoxy-6-nitrobenzofuran-2-carboxylate

Methyl 4-chloro-5-methoxybenzofuran-2-carboxylate was dissolved in conc.sulphuric acid (58 mL) with stirring in an ice bath then conc. nitricacid was added dropwise, maintaining the temperature below 5° C. Thereaction was then stirred at room temperature for 2.5 h. The reactionwas added to ice water (500 mL) over 2 h. The resulting solid wasfiltered and washed with water until neutral. The solid was dried toafford methyl 4-chloro-5-methoxy-6-nitrobenzofuran-2-carboxylate (6.3 g,91%), which was taken through to the next step with no furtherpurification.

Step 4: 4-Chloro-5-methoxy-6-nitrobenzofuran-2-carboxylic acid

Lithium hydroxide (0.9 g, 21.0 mmol) was added to a stirred suspensionof methyl 4-chloro-5-methoxy-6-nitrobenzofuran-2-carboxylate (2.0 g, 7.0mmol) in methanol-water (3:1) (40 mL). The reaction was allowed to stirfor 3 h at room temperature. The reaction was then concentrated underreduced pressure and the resulting residue was dissolved in water andwashed with diethyl ether. The aqueous phase was acidified by theaddition of 2M aqueous hydrochloric acid then extracted with ethylacetate. The combined organic extracts were passed through a phaseseparation cartridge and evaporated to afford a white solid (1.17 g,61%), which was taken through to the next step with no furtherpurification.

Step 5: 4-Chloro-5-methoxy-N,N-dimethyl-6-nitrobenzofuran-2-carboxamide

4-Chloro-5-methoxy-N,N-dimethyl-6-nitrobenzofuran-2-carboxamide wasprepared by the procedure described in Example 1, step 2 starting from4-chloro-5-methoxy-6-nitrobenzofuran-2-carboxylic acid (1.17 g, 4.31mmol) an dimethylamine hydrochloride (386 mg, 4.74 mmol). Purificationvia silica gel column chromatography (20-100% ethyl acetate/isohexane)gave 4-chloro-5-methoxy-N,N-dimethyl-6-nitrobenzofuran-2-carboxamide asa orange solid (850 mg, 66%).

Step 6: 6-Amino-5-methoxy-N,N-dimethylbenzofuran-2-carboxamide

4-Chloro-5-methoxy-N,N-dimethyl-6-nitrobenzofuran-2-carboxamide (500 mg,1.68 mmol), TEA (184 mg, 1.83 mmol) and 10% palladium on charcoal (90mg) were stirred at room temperature in THF-DMF (2:1) (30 mL) under anatmosphere of hydrogen for 18 h. The reaction was recharged withhydrogen then allowed to stir for an additional 18 h. The catalyst wasremoved by filtration and the filtrate was concentrated under reducedpressure to afford a brown solid (400 mg, quant.), which was takenthrough to the next step with no further purification.

Step 7:5-Methoxy-N,N-dimethyl-6-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzofuran-2-carboxamide

5-Methoxy-N,N-dimethyl-6-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzofuran-2-carboxamidewas prepared by the procedure described in Example 2, starting from4-chloro-5-methoxy-N,N-dimethyl-6-nitrobenzofuran-2-carboxamide (220 mg,0.94 mmol). The crude material was submitted to preparative HLPC forpurification to give5-methoxy-N,N-dimethyl-6-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzofuran-2-carboxamide(40 mg, 21%). LCMS (10 cm_ESCI_Formic_MeCN): [MH⁺]=410 at 3.01 min. ¹HNMR δ(ppm) (400 MHz, d6-DMSO): 8.70 (1H, s), 8.28 (1H, s), 8.17 (1H, s),7.40-7.32 (3H, m), 3.98 (3H, s), 3.41-3.28 (6H, m), 3.01 (3H, s).

Example 45-Chloro-1,3-dimethyl-6-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-benzo[d]imidazol-2(311)-oneStep 1: 5-Chloro-6-nitro-1H-benzo[d]imidazol-2(3H)-one

A stirred solution of 4-chloro-5-nitro-1,2-phenylenediamine (2.0 g,10.66 mmol) and CDI (2.59 g, 16 mmol) in anhydrous THF (50 mL) washeated to 85° C. for 4 h. The reaction was allowed to cool and thesolvents were removed under reduced pressure. The resulting residue waswashed with 2M aqueous hydrochloric acid and recrystallised frommethanol to afford 5-chloro-6-nitro-1H-benzo[d]imidazol-2(3H)-one as abrown solid (1.9 g, 84%), which was taken through to the next step withno further purification.

Step 2: 5-Chloro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one

5-Chloro-6-nitro-1H-benzo[d]imidazol-2(3H)-one (1.00 g, 4.7 mmol) wasstirred in DMF (50 mL) then potassium carbonate (1.29 g, 9.4 mmol) andiodomethane (2.66 g, 18.7 mmol) were added. The reaction was stirred at75° C. for 1.5 h. The reaction was allowed to cool and solvents wereremoved under reduced pressure. The residue was partitioned betweenwater and ethyl acetate and the phases were separated. The aqueous phasewas extracted with ethyl acetate and the combined organic extracts werethrough a phase separation cartridge and evaporated to afford a brownsolid (1.07 g, 95%), which was taken through to the next step with nofurther purification.

Step 3: 5-Amino-6-chloro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

5-Amino-6-chloro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one was preparedby the procedure described in Example 2, step 4 starting from5-chloro-6-nitro-1H-benzo[d]imidazol-2(3H)-one (400 mg, 1.64 mmol) toafford a brown solid (314 mg, 90%), which was taken through to the nextstep with no further purification.

Step 4:5-Chloro-1,3-dimethyl-6-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-benzo[d]imidazol-2(3H)-one

5-Chloro-1,3-dimethyl-6-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-benzo[d]imidazol-2(3H)-onewas prepared by the procedure described in Example 2, starting from5-amino-6-chloro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one (200 mg,0.94 mmol). Purification via silica gel column chromatography (0-100%ethyl acetate/isohexane) afforded the title compound (20 mg, 11%). LCMS(10 cm_ESCI_Formic_MeCN): [MH⁺]=387 at 3.10 min. ¹H NMR δ (ppm)(400 MHz,DMSO-d6): 8.83 (1H, s), 8.13 (1H, s), 7.58 (1H, s), 7.38 (1H, s), 7.08(1H, s), 3.36 (6H, s), 2.84 (3H, d, J=4.2).

Example 55-Chloro-3-methyl-6-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzo[d]oxazol-2(3H)-oneStep 1: 5-Chloro-6-nitrobenzo[d]oxazol-2(3H)-one

5-Chloro-6-nitrobenzo[d]oxazol-2(3H)-one was prepared by the proceduredescribed in Example 4, step 1 starting from2-amino-4-chloro-5-nitrophenol (5.53 g, 29.3 mmol), to afford a brownsolid (5.25 g, 83%), which was taken through to the next step with nofurther purification.

Step 2: 5-Chloro-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one

5-Chloro-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one was prepared by theprocedure described in Example 2, step 2 starting from5-chloro-6-nitrobenzo[d]oxazol-2(3H)-one (1.75 g, 8.1 mmol) substitutingiodomethane for dimethylsulfate. The crude product was recrystallisedfrom methanol to afford an orange solid (0.6 g, 32%), which was takenthrough to the next step with no further purification.

Step 3: 6-Amino-5-chloro-3-methylbenzo[d]oxazol-2(3H)-one

6-Amino-5-chloro-3-methylbenzo[d]oxazol-2(3H)-one was prepared by theprocedure described in Example 2, step 4 starting from5-chloro-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (520 mg, 2.3 mmol) toafford a solid (400 mg, 88%), which was taken through to the next stepwith no further purification.

Step 4:5-Chloro-3-methyl-6-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzo[d]oxazol-2(3H)-one

5-Chloro-3-methyl-6-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzo[d]oxazol-2(3H)-onewas prepared by the procedure described in Example 2, step 5 startingfrom 6-amino-5-chloro-3-methylbenzo[d]oxazol-2(3H)-one (224 mg, 1.1mmol). Purification via silica gel column chromatography (0-100% ethylacetate/isohexane) gave a solid which was triturated with petroleumether-diethyl ether (1:1) to afford a white solid (15 mg, 7%). LCMS (10cm_ESCI_Formic_MeCN): [MH⁺]=374 at 3.58 min. ¹H NMR δ (ppm) (400 MHz,CDCl₃): 8.57 (1H, s), 8.19 (1H, s), 7.48 (1H, s), 7.01 (1H, s), 5.28(1H, s), 3.39 (3H, s), 3.09 (3H, d, J=4.67).

Example 6N²-(6-chloro-2-methylbenzo[d]oxazol-5-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamineStep 1: 6-Chloro-2-methylbenzo[d]oxazol-5-amine

6-Chloro-2-methylbenzo[d]oxazol-5-amine was prepared by the proceduredescribed in Example 2, step 4 starting from6-chloro-2-methyl-5-nitrobenzo[d]oxazole (493 mg, 2.3 mmol) to afford asolid (200 mg, 47%). This was taken through to the next step with nofurther purification.

Step 2:N²-(6-chloro-2-methylbenzo[d]oxazol-5-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

N²-(6-chloro-2-methylbenzo[d]oxazol-5-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diaminewas prepared by the procedure described in Example 2, step 5 startingfrom 6-chloro-2-methylbenzo[d]oxazol-5-amine (205 mg, 1.1 mmol).Purification via silica gel column chromatography (0-100% ethylacetate/isohexane) gave a solid which was triturated with petroleumether-diethyl ether (1:1) to afford a white solid (15 mg, 7%). LCMS (10cm_ESCI_Formic_MeCN): [MH+]=358 at 3.49 min. ¹H NMR δ (ppm) (400 MHz,d6-DMSO): 8.90 (1H, s), 8.19 (2H, d, J=11.5), 7.87 (1H, s), 7.19 (1H, d,J=5.2), 2.86 (3H, d, J=4.3), 2.65 (3H, s).

Example 75-Methoxy-2-methyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one

A mixture of impure 6-amino-5-methoxy-2-methylisoindolin-1-one (<0.57mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (66 mg,0.31 mmol) and pTSA (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to100° C. for 4 h. DCM (10 mL) and saturated aqueous NaHCO₃ (10 mL) wereadded and the organic phase was passed through a hydrophobic frit andthe solvent was removed in vacuo. Purification of the residue viareversed phase preparative HPLC gave5-methoxy-2-methyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one(15 mg, 13%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN):[M+H]⁺=368 at 2.89 min. ¹H NMR (400 MHz, CDCl₃): δ 9.04 (s, 1H), 8.17(s, 1H), 7.80 (s, 1H), 6.93 (s, 1H), 5.26 (br s, 1H), 4.31 (s, 2H), 3.97(s, 3H), 3.20 (d, J 4.7, 3H), 3.18 (s, 3H).

Example 86-Chloro-5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-2-methylisoindolin-1-one

A mixture of 5-amino-6-chloro-2-methylisoindolin-1-one (61 mg, 0.31mmol), 2,5-dichloro-4-methoxypyrimidine (55 mg, 0.31 mmol) and pTSA (59mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 18 h. DCM (10mL) and saturated aqueous NaHCO₃ (10 mL) were added and the mixture waspassed through a hydrophobic frit. The solvent was removed in vacuo andpurification of the residue via reversed phase preparative HPLC gave6-chloro-5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-2-methylisoindolin-1-one(26 mg, 25%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN):[M+H]⁺=338 at 2.83 min. ¹H NMR (400 MHz, d6-DMSO): δ 8.46 (s, 1H), 8.29(s, 1H), 8.01 (s, 1H), 7.73 (s, 1H), 7.41 (q, J 4.6, 1H), 4.48 (s, 2H),3.08 (s, 3H), 2.91 (d, J 4.6, 3H).

Example 96-Chloro-2-methyl-5-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one

6-Chloro-2-methyl-5-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-onewas prepared according to the procedure described for Example 8, using2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine. LCMS (10cm_ESCI_Formic_MeCN): [M+H]⁺=372 at 3.48 min. ¹H NMR (400 MHz, d6-DMSO):δ 8.91 (s, 1H), 8.23 (s, 1H), 8.23 (s, 1H), 7.75 (s, 1H), 7.26 (q, J4.5, 1H), 4.49 (s, 2H), 3.09 (s, 3H), 2.88 (d, J 4.5, 3H).

Example 104-methoxy-2-methyl-5-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one

To a solution of 5-amino-4-methoxy-2-methylisoindolin-1-one (81 mg, 0.42mmol) in t-BuOH (3 mL) was added2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (89 mg, 0.42mmol). The mixture was heated at 100° C. for 1 h under microwaveirradiation. The solvent was evaporated in vacuo and the residue waspurified by reverse-phase prep-HPLC to afford the title compound as awhite solid (35 mg, yield 23%). m/z (ES+APCI)⁺: [M+H]⁺368.1. ¹H-NMR(Bruker, 500 MHz, MeOD) δ 8.65 (d, J=8.5 Hz, 1H), 8.13 (s, 1H), 7.43 (d,J=8.5 Hz, 1H), 4.69 (s, 2H), 4.06 (s, 3H), 3.19 (s, 3H), 3.05 (s, 3H)

The above compounds, together with additional compounds made using theabove procedures, are shown below in Table 3 together with LRRK2 Kivalues (micromolar).

TABLE 3 Structure Name H¹ NMR K_(i)  1

7-chloro-4-methyl-8- (4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)- 3,4-dihydrobenzo[f][1,4] oxazepin-5(2H)-one ¹H NMRδ (ppm)(400 MHz, CDCl₃): 8.41 (1 H, s), 8.22 (1 H, s), 7.97 (1 H, s),7.77- 7.67 (1 H, m), 5.29 (1 H, s), 4.47-4.39 (2 H, m), 3.61- 3.51 (2 H,m), 3.21-3.18 (3 H, m), 3.20-3.07 (3 H, m). 0.003  2

7-((5-chloro-4- (methylamino) pyrimidin-2-yl)amino)-6- methoxy-2,2,4-trimethyl-2H- benzo[b][1,4]oxazin- 3(4H)-one ¹H NMR δ (ppm)(400 MHz,DMSO): 8.05 (1 H, s), 7.98 (1 H, s), 7.54 (1 H, s), 7.28 (1 H, d, J =5.19 Hz), 6.85 (1 H, s), 3.93 (3 H, s), 3.66 (3 H, s), 2.91 (3 H, d, J =4.55 Hz), 1.41 (6 H, s). 0.001  3

5-methoxy-N,N- dimethyl-6-((4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- yl)amino)benzofuran- 2-carboxamide ¹H NMR δ (ppm)(400 MHz,DMSO): 8.70 (1 H, s), 8.28 (1 H, s), 8.17 (1 H, s), 7.40- 7.32 (3 H, m),3.98 (3 H, s), 3.41-3.28 (6 H, m), 3.01 (3 H, d). 0.001  4

5-chloro-1,3-dimethyl- 6-((4-(methylamino)- 5- (trifluoromethyl)pyrimidin-2-yl)amino)-1H- benzo[d]imidazol- 2(3H)-one ¹H NMR δ (ppm)(400MHz, DMSO-d₆): 8.83 (1 H, s), 8.13 (1 H, s), 7.58 (1 H, s), 7.38 (1 H,s), 7.08 (1 H, s), 3.36 (6 H, s), 2.84 (3 H, d, J = 4.21 Hz). 0.002  5

5-chloro-3-methyl-6- ((4-(methylamino)-5- (trifluoromethyl) pyrimidin-2-yl)amino)benzo[d] oxazol-2(3H)-one ¹H NMR δ (ppm)(400 MHz, CDCl₃): 8.57(1 H, s), 8.19 (1 H, s), 7.48 (1 H, s), 7.01 (1 H, s), 5.28 (1 H, s),3.39 (3 H, s), 3.09 (3 H, s). 0.004  6

N²-(6-chloro-2- methylbenzo[d]oxazol- 5-yl)-N⁴-methyl-5-(trifluoromethyl) pyrimidine-2,4-diamine ¹H NMR δ (ppm)(400 MHz, DMSO):8.90 (1 H, s), 8.19 (2 H, d, J = 11.50 Hz), 7.87 (1 H, s), 7.19 (1H, d,J = 5.17 Hz), 2.86 (3 H, d, J = 4.33 Hz), 2.65 (3 H, s). 0.005  7

5-methoxy-2-methyl- 6-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)isoindolin-1- one ¹H NMR (400 MHz, CDCl₃): δ 9.04 (s, 1H), 8.17(s, 1H), 7.80 (s, 1H), 6.93 (s, 1H), 5.26 (br s, 1H), 4.31 (s, 2H), 3.97(s, 3H), 3.20 (d, J = 4.7 Hz, 3H), 3.18 (s, 3H). 0.005  8

6-chloro-5-(5-chloro- 4- (methylamino) pyrimidin-2-ylamino)-2-methylisoindolin-1- one ¹H NMR (400 MHz, DMSO): δ 8.46 (s, 1H), 8.29 (s,1H), 8.01 (s, 1H), 7.73 (s, 1H), 7.41 (q, J = 4.6 Hz, 1H), 4.48 (s, 2H),3.08 (s, 3H), 2.91 (d, J = 4.6 Hz, 3H). 0.003  9

6-chloro-2-methyl-5- (4-(methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)isoindolin-1- one ¹H NMR (400 MHz, DMSO): δ 8.91 (s, 1H), 8.23(s, 1H), 8.23 (s, 1H), 7.75 (s, 1H), 7.26 (q, J = 4.5 Hz, 1H), 4.49 (s,2H), 3.09 (s, 3H), 2.88 (d, J = 4.5 Hz, 3H). 0.001 10

2-cyclopropyl-4- methoxy-5-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)isoindolin-1- one 0.007 11

4-methoxy-2-methyl- 5-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)isoindolin-1- one 0.001 12

6-methoxy-2,2,4- trimethyl-7-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)-2H- benzo[b][1,4]oxazin- 3(4H)-one ¹H NMR δ(ppm)(DMSO- d₆): 8.21 (1 H, s), 8.00 (1 H, s), 7.90 (1 H, s), 7.18 (1 H,d, J = 5.15 Hz), 6.86 (1 H, s), 3.35 (3H, s), 3.92 (3 H, s), 2.92 (3 H,s), 1.41 (6 H, s). 0.008 13

5-chloro-6-(5-chloro- 4- (methylamino) pyrimidin-2- ylamino)benzo[d]oxazol-2(3H)-one ¹H NMR δ (ppm)(400 MHz, CDCl₃): 8.53 (1 H, s), 7.90 (1H, s), 7.06-7.02 (1 H, m), 5.47 (1 H, s), 3.09 (4 H, m) 0.004 14

5-chloro-6-(5-chloro- 4- (methylamino) pyrimidin-2-ylamino)-3-methylbenzo[d]oxazol- 2(3H)-one ¹H NMR δ (ppm)(DMSO- d₆): 8.30 (1 H, s),7.90 (2 H, d, J = 4.87 Hz), 7.51 (1 H, s), 7.29-7.22 (1 H, m), 3.36 (3H, s), 2.86 (3 H, d, J = 4.52 Hz). 0.002 15

7-methoxy-2-methyl- 6-(4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)-3,4- dihydroisoquinolin- 1(2H)-one 0.007 16

2-(7-methoxy-2- methyl-1-oxo-1,2,3,4- tetrahydroisoquinolin-6-ylamino)-4- (methylamino) pyrimidine-5-carbonitrile 0.044 17

7-methoxy-2-methyl- 6-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)phthalazin- 1(2H)-one 0.027 18

2-ethyl-4-methoxy-5- (4-(methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)isoindolin-1- one 0.009 19

2-(2-hydroxypropan- 2-yl)-4-methoxy-5-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)isoindolin-1- one 0.004 20

4-methoxy-5-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)-2- (oxetan-3- yl)isoindolin-1-one 0.009 21

6-methoxy-2-methyl- 5-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)isoindolin-1- one 0.005 22

(5-chloro-1-methyl-6- (4-(methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- indol-3- yl)(morpholino) methanone 0.003 23

2-(2-hydroxy-2- methylpropyl)-6- methoxy-5-(4- (methylamino)-5-(trifluoromethyl) pyrimidin-2- ylamino)isoindolin-1- one 0.01 24

5-(4-(ethylamino)-5- (trifluoromethyl) pyrimidin-2- ylamino)-2-(2-hydroxy-2- methylpropyl)-6- methoxyisoindolin-1- one 0.003 25

6-methoxy-5-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)-2- (oxetan-3- yl)isoindolin-1-one 0.006 26

5-(4-(ethylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-6-methoxy-2-(oxetan-3- yl)isoindolin-1-one 0.002 27

5-chloro-N,N,1- trimethyl-6-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- indole-3-carboxamide 0.006 28

(5-chloro-1-methyl-6- (4-(methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- indol-3-yl)(piperazin- 1-yl)methanone 0.004 29

(5-chloro-6-(4- (ethylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)-1- methyl-1H-indol-3- yl)morpholino) methanone0.001 30

(5-methoxy-1-methyl- 6-(4-(methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)-1H- indol-3- yl)(morpholino) methanone 0.001 31

(5-chloro-1-methyl-6- (4-(methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H- indol-3-yl)(4- methylpiperazin-1- yl)methanone 0.001 32

(5-chloro-1-methyl-6- (4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)- 1H-indol-3-yl)(4- ethylpiperazin-1- yl)methanone0.001 33

(1S,4S)-2-oxa-5- azabicyclo[2.2.1] heptan-5-yl(5-chloro-1- methyl-6-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)-1H-indol-3-yl)methanone 0.003 34

4-methoxy-2-methyl- 5-(4-(methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)isoindolin-1- one 35

(5-methoxy-6-(4- (methylamino)-5- (trifluoromethyl) pyrimidin-2-ylamino)benzofuran- 3- yl)(morpholino) methanone 36

5-methoxy-N,N- dimethyl-6-(4- (methylamino)-5- (trifluoromethyl)pyrimidin-2- ylamino)benzofuran- 3-carboxamide

Example 10 In Vitro LRRK2 LabChip Assay

This assay was used to determine a compound's potency in inhibitingactivity of LRRK2 by determining, Ki_(app), IC₅₀, or percent inhibitionvalues. In a polypropylene plate, LRRK2, fluorescently-labeled peptidesubstrate, ATP and test compound were incubated together. Using aLabChip 3000 (Caliper Life Sciences), after the reaction the substratewas separated by capillary electrophoresis into two populations:phosphorylated and unphosphorylated. The relative amounts of each werequantitated by fluorescence intensity. LRRK2 Ki was determined accordingto the equation:

Y=V0*(1−((x+Ki*(1+S/Km)+Et)/(2*Et)−(((x+Ki*(1+S/Km)+Et)̂2−(4*Et*x))̂0.5)/(2*Et))).

Ki values in Table 4 and elsewhere herein are shown in μM.

Assay conditions and materials used were as follows:

Final Assay Conditions:

LRRK2 G2019S in 5 mM MgCl₂: 5.2 nM (Invitrogen lot #567054A)

LRRK2 G2019S in 1 mM MnCl₂: 11 nM (Invitrogen lot #567054A)

LRRK2 Wild type in 5 mM MgCl₂: 15 nM (Invitrogen lot #500607F)

LRRK2 I2020T in 5 mM MgCl₂: 25 nM (Invitrogen lot #43594)

Substrate: 1 μM

ATP: 130 μM

Kinase reaction time: 2 hours

Temperature: ambient

Total volume: 20 μl

ATP^(app) Kms:

G2019S in 5 mM MgCl₂: 130 μM

G2019S in 1 mM MnCl₂: 1 μM

Wild type in 5 mM MgCl₂: 80 μM

I2020T in 5 mM MgCl₂: 14 μM

Materials:

Solid Support: Black 50 μL volume polypropylene 384 well plate (MatriCalcat #MP101-1-PP)

Kinase: LRRK2 G2019S (Invitrogen cat #PV4882).

-   -   LRRK2 Wild type (Invitrogen cat #PV4874).

Substrate: 5FAM-GAGRLGRDKYKTLRQIRQ-CONH₂

Non-binding plate: 384 well clear V-bottom polypropylene plates (Greinercat #781280).

ATP: 10 mM ATP (Cell Signaling cat #9804).

Triton X-100: Triton X-100.

Brij-35: Brij-35 (Pierce cat #20150).

Coating Reagent #3: Coating Reagent #3 (Caliper).

DMSO: DMSO (Sigma cat #34869-100 mL).

Complete Reaction Buffer: H₂O/25 mM Tris, pH 8.0/5 mM MgCl₂/2 mMDTT/0.01% Triton X-100.

Stop Solution: H₂O/100 mM HEPES, pH 7.2/0.015% Brij-35/0.2% CoatingReagent #3/20 mM EDTA.

Separation Buffer: H₂O/100 mM HEPES, pH 7.2/0.015% Brij-35/0.1% CoatingReagent #3/1:200 Coating Reagent #8/10 mM EDTA/5% DMSO.

Compound Plate Preparation:

For serial dilutions, 34.6 μl DMSO was added to columns 3-24. For theassay controls, 37.5 μl DMSO was added to columns 1 and 2 of rows A andP. a,d and 50 μl 25 μM G-028831 (Staurosporine) was added to columns 1and 2, row B. For the samples: to start at 100 μM, 37.5 μl DMSO was tocolumns 1 and 2, then 12.5 μl 10 mM compound; to start at 10 μM, 78 μlDMSO was added to columns 1 & 2, then 2 μl 10 mM compound; and to startat 1 μM, 25 μM compound (2 μl 10 mM cmpd+798 μl DMSO) was added to emptycolumns 1 and 2. A Precision instrument was used to perform 1:3.16serial dilutions (“PLK_BM_serial_halflog”).

ATP Preparation:

ATP was diluted to 282.1 μM in Complete Kinase Buffer (finalconcentration was 130 μM).

Total and Blank Preparation:

In Complete Reaction Buffer, substrate was diluted to 4 μM. Equalvolumes of Complete Reaction Buffer and 4 μM substrate were combined toobtain the blank. Equal volumes of Complete Reaction Buffer and 4 μMsubstrate were combined and to the combined solution was added 2× finalLRRK2 concentration.

Assay Procedure:

To a 50 μA polypropylene plate, 5 μl/well buffer/substrate was added byhand to Blank wells. A Biomek FX was used to start the kinase reaction(“PLK SAR 23 ATP”). The following were added to the appropriate wells:

2 μA compound+23 μA ATP;

5 μl/well compound/ATP in Assay Plate;

5 μl/well kinase/substrate in Assay Plate;

The plate was incubated for 2 hours in the dark. Biomek FX was used tostop the kinase reaction (“PLK Stop”), and 10 μl/well Stop solution wasadded to the Assay Plate.Results were read on the LabChip 3000.

Lab Chip 3000 Protocol:

The LabChip 3000 was run using the job “LRRK2 IC50” with the followingjob settings:

Pressure: −1.4 psi

Downstream voltage: −500 V

Upstream voltage: −2350 V

Post sample buffer sip time: 75 seconds

Post dye buffer sip time: 75 seconds

Final delay time: 200 seconds

Example 11 In Vitro LRRK2 Lanthascreen Binding Assay

This assay was used to determine a compound's potency in inhibitingactivity of LRRK2 by determining, Ki_(app), IC₅₀, or percent inhibitionvalues. In 384 well proxiplates F black, shallow well plates LRRK2,Eu-anti-GST-antibody, Alexa Fluor® Kinase tracer 236 and test compoundwere incubated together.

Binding of the Alexa Fluor® “tracer” to a kinase was detected byaddition of a Eu-labeled anti-GST antibody. Binding of the tracer andantibody to a kinase results in a high degree of FRET, whereasdisplacement of the tracer with a kinase inhibitor results in a loss ofFRET.

Assay conditions and materials used were as follows:

Final Assay Conditions:

GST-LRRK2 G2019S 10 nM

Eu-anti-GST-antibody 2 nM

Kinase tracer 236 8.5 nM

Kinase reaction time: 1 hour

Temperature: ambient

Total volume: 15 μl

DMSO 1%

Materials:

384 well proxiplates F black shallow well Perkin Elmer cat#6008260

Kinase: LRRK2 G2019S Invitrogen cat #PV4882(LOT 567054A).

Eu-labeled anti-GST antibody Invitrogen cat #PV5594

Alexa Fluor® Kinase tracer 236 Invitrogen cat #PV5592

TRIS-HCl Sigma cat #T3253

EGTA Sigma cat #E3889

Brij-35: Sigma cat #B4184(30% w/v)

DMSO: Sigma cat #D8418

MgCl₂ Sigma cat #M9272

Reaction Buffer: H₂O/50 mM Tris, pH 7.4/10 mM MgCl₂/1 mM EGTA/0.01% Brij35.

Compound Plate Preparation:

Serially dilute test compounds (10 mM stock) 1:3.16 (20 ul+43.2 ul) in100% DMSO. 12 pt curve. Dilute each concentration 1:33.3 (3 ul+97 ul) inreaction buffer. Stamp 5 ul to assay plate. Final top test concentration100 uM.

Total and Blank Preparation:

In Reaction Buffer, 5 ul of DMSO (3%) was added to total and blank wellsand 5 ul of Eu-labeled anti-GST antibody (6 nM) was added to blankwells.

Assay Procedure:

Add 5 ul LRRK2(30 nM)/Eu-labeled anti-GST antibody (6 nM) mix tocompound and total wells. Add 5 ul kinase tracer (25.5 nM) to all wells.Incubate plates at room temperature for 1 hour on a plate shaker (gentleshaking). Read on Perkin Elmer EnVision reader HTRF protocol.

Data Handling:

Calculate ratio: (665/620)*10000. Substract mean background values fromall data points. Calculate % of control for each test value. Plot % ofcontrol vs Compound concentration. Calculate Ki Value (xlfit curvefitting—Morrison equation).

Results expressed as a Ki in μM. The equation for Ki:Y=V0*(1−((x+Ki*(1+S/Km)+Et)/(2*Et)−(((x+Ki*(1+S/Km)+Et)̂2−(4*Et*x))̂0.5)/(2*Et)))

Where Et=4 nM

kd (Tracer)=8.5 nM

Tracer concentration (S)=8.5 nM.

Example 12 Parkinson's Disease Animal Model

Parkinson's disease can be replicated in mice and in primates byadministration of 1-methyl-4-phenyl tetrahydropyridine (MPTP), aselective nigrostriatal dopaminergic neurotoxin that produces a loss ofstriatal dopamine (DA) nerve terminal markers. Compounds of theinvention may be evaluated for effectiveness in treatment of Parkinson'sdisease using MPTP induced neurodegeneration following generally theprotocol described by Saporito et al., J. Pharmacology (1999) Vol. 288,pp. 421-427.

Briefly, MPTP is dissolved in PBS at concentrations of 2-4 mg/ml, andmice (male C57 weighing 20-25 g) are given a subcutaneous injection of20 to 40 mg/kg. Compounds of the invention are solubilized withpolyethylene glycol hydroxystearate and dissolved in PBS. Mice areadministered 10 ml/kg of compound solution by subcutaneous injection 4to 6 h before MPTP administration, and then daily for 7 days. On the dayof the last injection, mice are sacrificed and the midbrain blocked andpostfixed in paraformaldehyde. Striata are dissected free, weighed, andstored at −70° C.

The striata thus collected are evaluated for content of dopamine and itsmetabolites dihydroxyphenylacetic acid and homovanillic acid, by HPLCwith electrochemical detection as described by Sonsalla et al., J.Pharmacol. Exp. Ther. (1987) Vol. 242, pp. 850-857. The striata may alsobe evaluated using the tyrosine hydroxylase assay of Okunu et al., AnalBiochem (1987) Vol. 129, pp. 405-411 by measuring ¹⁴CO₂ evolutionassociated with tyrosine hydroxylase-mediated conversion of labeledtyrosine to L-dopa. The striata may further be evaluated using theMonoamine oxidase-B assay as described by White et al., Life Sci.(1984), Vol. 35, pp. 827-833, and by monitoring dopamine uptake asdescribed by Saporito et al., (1992) Vol. 260, pp. 1400-1409.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound of formula I:

or pharmaceutically acceptable salts thereof, wherein: A is a five- orsix-membered saturated or unsaturated ring that includes one or twoheteroatoms selected from O, N and S, which is substituted once with R⁵,and which is optionally substituted one, two or three times with R⁶; Xis: —NR^(a)—; —O—; or —S(O)_(r)— wherein r is from 0 to 2 and R^(a) ishydrogen or C₁₋₆alkyl; R¹ is: C₁₋₆alkyl; C₁₋₆alkenyl; C₁₋₆alkynyl;halo-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;amino-C₁₋₆alkyl; C₁₋₆alkylsulfonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl optionallysubstituted with C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆alkyl; oxetanyl; oroxetan-C₁₋₆alkyl; or R¹ and R^(a) together with the atoms to which theyare attached may form a three to six membered ring that may optionallyinclude an additional heteroatom selected from O, N and S, and which issubstituted with oxo, halo or C₁₋₆alkyl; R² is: halo; C₁₋₆alkoxy; cyano;C₁₋₆alkynyl; C₁₋₆alkenyl; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy;C₃₋₆cycloalkyl wherein the C₃₋₆cycloalkyl portion is optionallysubstituted with C₁₋₆alkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl wherein theC₃₋₆cycloalkyl portion is optionally substituted with C₁₋₆alkyl;tetrahydrofuranyl; tetrahydrofuranyl-C₁₋₆alkyl; acetyl; oxetanyl; oroxetan-C₁₋₆alkyl; one of R³ and R⁴ is: halo; C₁₋₆alkyl; C₁₋₆alkoxy;C₃₋₆cycloalkyloxy; halo-C₁₋₆alkyl; or halo-C₁₋₆alkoxy, and the other ishydrogen; R⁵ is; oxo; C₁₋₆alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; or —C(O)—NR^(b)R^(c) wherein R^(b) and R^(c)each independently is hydrogen or —C₁₋₆alkyl, or R^(b) and R^(c)together with the atoms to which they are attached may form aheterocyclyl group that optionally includes an additional heteroatomselected from O, N and S and which is optionally substituted one or moretimes with R⁶; and each R⁶ is independently: C₁₋₆alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; halo; halo-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; heterocyclyl; oxo; or —C(O)—NR^(b)R^(c).
 2. Thecompound of claim 1, wherein X is —NH— or —O—.
 3. The compound of claim1, wherein R¹ is C₁₋₆alkyl.
 4. The compound of claim 1, wherein R² is:halo; halo-C₁₋₆alkyl; or cyano.
 5. The compound of claim 1, wherein R²is chloro, trifluoromethyl or cyano.
 6. The compound of claim 1, whereinR² is trifluoromethyl.
 7. The compound of claim 1, wherein R³ is halo orC₁₋₆alkoxy.
 8. The compound of claim 1, wherein R³ is halo or methoxy.9. The compound of claim 1, wherein R⁴ is halo or C₁₋₆alkoxy.
 10. Thecompound of claim 1, wherein R⁴ is halo or methoxy.
 11. The compound ofclaim 1, wherein R⁵ is: oxo; C₁₋₆alkyl; or —C(O)—NR^(b)R^(c).
 12. Thecompound of claim 1, wherein each R⁶ is independently: C₁₋₆alkyl.hydroxy-C₁₋₆alkyl. C₁₋₆alkoxy-C₁₋₆alkyl. heterocyclyl. oxo. or—C(O)—NR^(b)R^(c).
 13. The compound of claim 1, wherein said compound isof formula IIa or IIb:

wherein: m is: 0; 1 or 2; Z is; —C(R⁷)₂—; —NR⁸— or —O—; or Z is absent;each R⁷ is independently: hydrogen; or C₁₋₆alkyl; and each R⁸ isindependently: hydrogen; C₁₋₆alkyl; C₃₋₆cycloalkyl;C₃₋₆cycloalkyl-C₁₋₆alkyl; halo; halo-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl;C₁₋₆alkoxy-C₁₋₆alkyl; heterocyclyl; or —C(O)—NR^(b)R^(c).
 14. Thecompound of claim 1, wherein m is 0 or
 1. 15. The compound of claim 1,wherein Z is —C(R⁷)₂—.
 16. The compound of claim 1, wherein Z is —NR⁸—.17. The compound of claim 1, wherein Z is —O—.
 18. The compound of claim1, wherein Z is absent.
 19. A composition comprising: (a) apharmaceutically acceptable carrier; and (b) a compound of claim
 1. 20.A method for treating Parkinson's disease, said method comprisingadministering to a subject in need thereof an effective amount of acompound of claim 1.